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Background Ultra-processed food (UPF) consumption is related to increased morbidity and mortality. However, knowledge on its association with cognitive function is lacking. In this longitudinal study, we examined the associations between UPF intake and cognitive decline in older adults with type-2 diabetes (T2D). Methods The sample included initially nondemented T2D older adults (≥65 years), from the Israel Diabetes and Cognitive Decline study, who had complete information on nutrition at baseline and at least 3 cognitive assessments (mean follow-up 5.3 ± 1.5 years). Nutritional intake was evaluated by a validated Food-Frequency Questionnaire, and foods were categorized as UPF based on NOVA classification. Percent of calories from UPF were calculated from total caloric consumption in total and specific food groups. Mixed effect models were used to examine the link between UPF intake (top vs bottom quartiles) and change in cognitive function overall and in specific domains, adjusting for potential confounders. Results Of the total sample (N = 568; mean age 71.3 ± 4.5 years, 60% men), 141 consumed >31% kcal from UPF (top quartile). Greater intake of ultra-processed meat was associated with a faster decline in executive functions and global cognition (β = −0.041 ± 0.013; p = .002 and β = −0.026 ± 0.010; p = .011, respectively). Additionally, consumption of ultra-processed oils/spreads was associated with faster decline in executive functions and global cognition (β = −0.037 ± 0.014; p = .006 and β = −0.028 ± 0.010; p = .009, respectively). Total UPF consumption and UPF-derived from dairy products and bread/pastries/starch were not associated with cognitive change. Conclusion This study suggests that a high intake of ultra-processed meat and oils/spreads may be associated with accelerated cognitive decline in older individuals with T2D.

IntroductionRecently, interest has emerged in subjective cognitive decline (SCD) as a potential precursor to Alzheimer’s disease (AD) dementia. Whether individuals with SCD harbor brain alterations in midlife, when AD-related pathology begins, is yet to be elucidated. Furthermore, the role of apolipoprotein ε4 (APOE ε4) allele, a robust AD risk factor, in the relationship between SCD and brain alterations is unknown. We examined whether APOE genotype modulates the association of SCD with brain measures in individuals at high AD risk.MethodsMiddle-aged adults with parental history of AD dementia underwent magnetic resonance imaging (MRI) and the Memory Functioning Questionnaire. Regression analysis tested the extent to which SCD was associated with activation during an functional MRI (fMRI) working-memory task, and white-matter microstructure. APOE ε4 genotype was tested as a moderator.ResultsAmong APOE ε4 carriers, but not among non-carriers, SCD was associated with higher activation in the anterior cingulate (p = 0.003), inferior, middle, and superior frontal cortices (p = 0.041, p = 0.048, p = 0.037, respectively); and with lower fractional anisotropy in the uncinate fasciculus (p = 0.002), adjusting for age, sex, and education.ConclusionIn middle aged, cognitively normal individuals at high AD risk, higher SCD was associated with greater brain alterations possibly reflecting incipient AD pathology. When accompanied by a family history of AD and an APOE ε4 allele, SCD may have important clinical value, allowing a window for early intervention and for participants’ stratification in AD prevention clinical trials.

Background We examined the cross-sectional and longitudinal relationships of motor functions with depression in older adults with type 2 diabetes (T2D). Methods Participants (n = 984) were from the longitudinal Israel Diabetes and Cognitive Decline (IDCD) study. They were initially cognitively normal and underwent evaluations of motor functions (grip strength and gait speed) and of depression (using the 15-item version of the Geriatric Depression Scale [GDS]) approximately every 18 months. We applied Hierarchical Linear Mixed Models (HLMM) to investigate the associations between motor functions and depression adjusting for sociodemographic, cardiovascular factors, overall cognitive score, and subjective report of exhaustion. Results Participants’ baseline characteristics were 72 (±5) years of age (59.6% males), 13 (±4) years of education, Mini-Mental Status Exam (MMSE) score of 28.01 (±1.78), and a GDS score of (2 ± 2.00), consistent with normal cognitive status and lack of major affective symptomatology. Slower gait speed at baseline was associated with higher GDS scores (p = .001) and with their increase over time (p = .049). A decrease in walking speed from baseline was associated with an increase in GDS scores (p = .015). Lower grip strength at baseline was associated with higher GDS scores (p = .002), but not with trajectories in GDS scores over time. A faster decrease in grip strength from baseline was associated with a faster increase in GDS scores (p = .022). Conclusions Both gait speed and grip strength are cross-sectionally associated with depression. However, only gait speed and its decrease over time can potentially be used to predict incident depression symptoms, thus facilitating the introduction of depression prevention strategies.

On behalf of the ISTAART Neuropsychiatric Syndromes Professional Interest Area Psychosis work group, this is a pre-registration for the Phenomenology, Epidemiology, Neurobiology, Prognosis, and Treatment Considerations of Late-Onset Psychosis paper.

Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials This manuscriptwas facilitated by the Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment (ISTAART), through the Neuropsychiatric Syndromes professional interest area (PIA). The views and opinions expressed by authors in this publication represent those of the authors and do not necessarily reflect those of the PIA membership, ISTAART or the Alzheimer’s Association. Ganesh M. Babulal receives research support from the BrightFocus Foundation (A2021142S), and NIH/NIA (R01AG074302 AG068183, AG067428, AG056466). Marie-Andr´ee Bruneau has received support from Optimizing Practices, Use, Care and Services - Antipsychotics (OPUS-AP) in Quebec, Canadian Foundation for Healthcare Improvement and Quebec Ministry of Health and Social services. Jennifer Gatchel has received research support from the BrightFocus Foundation, Alzheimer’s Association, and NIH/NIA. Zahinoor Ismail has received support from Brain Canada, Canadian Institutes of Health Research, and Canadian Consortium on Neurodegeneration in Dementia. Sanjeev Kumar has received support from Academic Scholars Award from the Department of Psychiatry, University of Toronto, Brain and Behavior Foundation, National institute on Ageing, BrightFocus Foundation, Brain Canada, Canadian Institute of Health Research, Canadian Consortium on Neurodegeneration in Aging, Centre for Ageing and Brain Health Innovation, Centre for Addiction and Mental Health, University of Toronto. Equipment support from Soterix Medical. Krista L. Lanctˆot has received support from the Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, National Institute on Ageing, Canadian Institutes of Health Research,Weston Brain Institute and the Canadian Consortium on Neurodegeneration in Aging. Moyra E. Mortby has received support from the Australian National Health and Medical Research Council (NHMRC) and Australian Research Council (ARC) Dementia Research Development Fellowship #1102028. Nicolas A. Nu˜nez has received support from the National Institute of General Medical Sciences of the National Institutes of Health under award number T32 GM008685. Fabricio Oliveira has received support from FAPESP – The State of S˜ao Paulo Research Foundation (grant #2015/10109-5). Authors’ disclosures available online (https:// www.j-alz.com/manuscript-disclosures/21-5483r2) SI

Physical fitness is an important contributor to healthy aging that improves cognition. Older adults who engage in cardiorespiratory fitness activities show less cognitive decline. To examine whether physical fitness acts as a potential protective mechanism shielding against the negative associations between age and cognition. Specifically, we examined whether physical fitness mediates the relationship between age and processing speed. 114 (M = 63.80, SD = 10.63) senior executives completed a computerized cognitive battery composed of four processing speed tasks. Level of physical fitness was assessed on a treadmill stress test and reported in metabolic equivalents (METs). Older age was associated with slower processing speed (r = 0.25, p = 0.007), whereas greater physical fitness was associated with faster processing speed (r = −0.30, p = 0.001). Path analysis indicated that the association between age and processing speed was fully mediated by the level of physical fitness (Indirect effect: β = 0.10, p = 0.008; Direct effect: β = 0.16, p = 0.20). The findings indicate that physical fitness is a strong mediator of the relationship between age and processing speed and imply that physical fitness makes a major contribution to cognitive reserve during the aging process. The results may suggest that the decrease in physical fitness during aging may partially account for slower cognitive processing.

Backgrounds The efficacy of vitamin E in prevention of diabetes-related complications differs by Haptoglobin (Hp) genotype. Objective To examine the role of Hp genotype in the relationship of vitamin E intake with brain volume in cognitively normal elderly patients with type 2 diabetes. Methods Brain volumes for the superior, middle, and inferior frontal gyri and for the middle temporal gyrus were generated from structural T1 MRI in 181 study participants (Hp 1-1: n = 24, Hp 2-1: n = 77, Hp 2-2: n = 80). Daily vitamin E intake was assessed using the Food Frequency Questionnaire. Analyses of covariance, controlling for demographic and cardiovascular variables was used to evaluate whether the association of daily vitamin E intake with brain volume was modified by Hp genotype. Results Average age was 70.8 (SD = 4.2) with 40% females, and mean Mini-Mental State Examination score of 28.17 (SD = 1.90). A significant interaction was found between vitamin E intake and Hp genotype in inferior frontal gyrus' volume; p = 0.0108. For every 1 microgram increase in vitamin E intake, the volume of the inferior frontal gyrus decreased by 0.955% for Hp 1-1 (p = 0.0348), increased by 0.429% for Hp 2-1 (p = 0.0457), and by 0.077% for Hp 2-2 (p = 0.6318). There were no significant interactions between vitamin E intake and Hp genotype for the middle (p = 0.6011) and superior (p = 0.2025) frontal gyri or for the middle temporal gyrus (p = 0.503). Conclusions The effect of dietary vitamin E on the brain may differ by Hp genotype. Studies examining the impact of vitamin E on brain-related outcomes should consider Hp genotype.

To determine associations of three dietary patterns (Mediterranean (MEDI) diet, the Dietary Approaches to Stop Hypertension (DASH) diet and the Mediterranean- DASH Intervention for Neurodegenerative Delay (MIND) diet) with cognitive decline in older adults with type 2 diabetes mellitus (T2D).This is a longitudinal observational study. Participants (N = 960) from the Israel Diabetes and Cognitive Decline (IDCD) study were included in this study. A multivariable-adjusted model including all three dietary patterns concurrently was developed to investigate their independent effect on cognitive decline.The mean follow up was 4.1 ± 2.1 years. While high adherence to both the MIND and the MEDI diet was associated with a slower decline, in the multivariable model only the associations of higher MEDI diet intake with greater decline in global cognition and in executive functions remained significant (β = 0.013, SE = 0.006; P = 0.042; β = 0.001, SE = 0.008, Pv = 0.023 respectively).In older adults with T2D, adherence to the MEDI is related to better cognitive trajectory. Diet is a meaningful factor in the path linking T2D and cognition.

Currently there are no reliable biomarkers for early detection of Alzheimer's disease (AD) at the preclinical stage. This study assessed the pupil light reflex (PLR) for focal red and blue stimuli in central and peripheral retina in 125 cognitively normal middle age subjects (45-71 YO) at high risk for AD due to a family history of the disease, and 61 age-similar subjects with no family history of AD using Chromatic Pupilloperimetry coupled with Machine Learning (ML). All subjects had normal ophthalmic assessment, and normal retinal and optic nerve thickness by optical coherence tomography. No significant differences were observed between groups in cognitive function and volumetric brain MRI. Chromatic pupilloperimetry-based ML models were highly discriminative in differentiating subjects with and without AD family history, using transient PLR for focal red (primarily cone-mediated), and dim blue (primarily rod-mediated) light stimuli. Features associated with transient PLR latency achieved Area Under the Receiver Operating Characteristic Curve of 0.90 ± 0.051 (left-eye) and 0.87 ± 0.048 (right-eye). Parameters associated with the contraction arm of the rod and cone-mediated PLR were more discriminative compared to parameters associated with the relaxation arm and melanopsin-mediated PLR. Taken together our study suggests that subtle focal changes in pupil contraction latency may be detected decades before the onset of AD clinical symptoms. The dendrites of melanopsin containing retinal ganglion cells may be affected very early at the preclinical stages of AD.

Currently there are no reliable biomarkers for early detection of Alzheimer's disease (AD) at the preclinical stage. This study assessed the pupil light reflex (PLR) for focal red and blue light stimuli in central and peripheral retina in 125 cognitively normal middle age subjects (45–71 years old) at high risk for AD due to a family history of the disease (FH+), and 61 age-similar subjects with no family history of AD (FH−) using Chromatic Pupilloperimetry coupled with Machine Learning (ML). All subjects had normal ophthalmic assessment, and normal retinal and optic nerve thickness by optical coherence tomography. No significant differences were observed between groups in cognitive function and volumetric brain MRI. Chromatic pupilloperimetry-based ML models were highly discriminative in differentiating subjects with and without AD family history, using transient PLR for focal red (primarily cone-mediated), and dim blue (primarily rod-mediated) light stimuli. Features associated with transient pupil response latency (PRL) achieved Area Under the Curve Receiver Operating Characteristic (AUC-ROC) of 0.90 ± 0.051 (left-eye) and 0.87 ± 0.048 (right-eye). Parameters associated with the contraction arm of the rod and cone-mediated PLR were more discriminative compared to parameters associated with the relaxation arm and melanopsin-mediated PLR. Significantly shorter PRL for dim blue light was measured in the FH+ group in two test targets in the temporal visual field in right eye that had highest relative weight in the ML algorithm (mean ± standard error, SE 0.449 s ± 0.007 s vs. 0.478 s ± 0.010 s, p = 0.038). Taken together our study suggests that subtle focal changes in pupil contraction latency may be detected in subjects at high risk to develop AD, decades before the onset of AD clinical symptoms. The dendrites of melanopsin containing retinal ganglion cells may be affected very early at the preclinical stages of AD.

ObjectivesMultiple risk loci for late-onset Alzheimer’s disease (LOAD) have been identified. Type 2 diabetes (T2D) is a risk factor for cognitive decline, dementia and Alzheimer’s disease (AD). We investigated the association of polygenic risk score (PRS) for LOAD with overall cognitive functioning and longitudinal decline, among older adults with T2D.MethodsThe study included 1046 Jewish participants from the Israel Diabetes and Cognitive Decline (IDCD) study, aged ≥ 65 years, diagnosed with T2D, and cognitively normal at baseline. The PRS included variants from 26 LOAD associated loci (at genome-wide significance level), and was calculated with and without APOE. Outcome measures, assessed in 18 months intervals, were global cognition and the specific domains of episodic memory, attention/working memory, executive functions, and language/semantic categorization. Random coefficient models were used for analysis, adjusting for demographic variables, T2D-related characteristics, and cardiovascular factors. Additionally, in a subsample of 202 individuals, we analyzed the association of PRS with the volumes of total gray matter, frontal lobe, hippocampus, amygdala, and white matter hyperintensities. Last, the association of PRS with amyloid beta (Aβ) burden was examined in 44 participants who underwent an 18F-flutemetamol PET scan.ResultsThe PRS was not significantly associated with overall functioning or decline in global cognition or any of the specific cognitive domains. Similarly, following correction for multiple testing, there was no association with Aβ burden and other brain imaging phenotypes.ConclusionOur results suggest that the cumulative effect of LOAD susceptibility loci is not associated with a greater rate of cognitive decline in older adults with T2D, and other pathways may underlie this link.

We compared retinal layers' thickness between apolipoprotein E (Participants (N = 245) underwent spectral domain optical coherence tomography. Multivariate analyses of covariance adjusting for age, sex, education, and best corrected vision acuity was used to compare retinal thickness betweenParticipants' mean age was 59.60 (standard deviation = 6.42) with 66.4% women and 32.2%A thicker macula is observed already in midlife asymptomatic

Aim: We investigated the relationship between midlife C-reactive protein (CRP) levels in men with coronary heart disease (CHD) and depressive symptoms at old age. CRP levels were measured in a subs...

Background To evaluate the effects of adaptive and tailored computerized cognitive training on cognition and disease self-management in older adults with diabetes. Methods This was a single-blind trial. Eighty-four community-dwelling older adults with diabetes were randomized into a tailored and adaptive computerized cognitive training or a generic, non-tailored or adaptive computerized cognitive training condition. Both groups trained for 8 weeks on the commercially available CogniFit program and were supported by a range of behavior change techniques. Participants in each condition were further randomized into a global or cognition-specific self-efficacy intervention, or to a no self-efficacy condition. The primary outcome was global cognition immediately following the intervention. Secondary outcomes included diabetes self-management, meta-memory, mood, and self-efficacy. Assessments were conducted at baseline, immediately after the training, and at a 6-month follow-up. Results Adherence and retention were lower in the generic computerized cognitive training condition, but the self-efficacy intervention was not associated with adherence. Moderate improvements in performance on a global cognitive composite at the posttreatment assessments were observed in both cognitive training conditions, with further small improvement observed at the 6-month follow-up. Results for diabetes self-management showed a modest improvement on self-rated diabetes care for both intervention conditions following the treatment, which was maintained at the 6-month follow-up. Conclusions Our findings suggest that older adults at higher dementia risk due to diabetes can show improvements in both cognition and disease self-management following home-based multidomain computerized cognitive training. These findings also suggest that adaptive difficulty and individual task tailoring may not be critical components of such interventions. Trial registration NCT02709629.

Background Objective and subjective health are two powerful constructs which predict morbidity and mortality across a range of conditions including Type 2 Diabetes (T2D). Studies, however, suggest that these two constructs do not necessarily correlate, as some people with poor objective health perceive their health as good, while other people with good objective health perceive their health as poor. We seek to examine the role of personality as a moderator of the associations between objective and subjective health among older adults with T2D, who are likely to experience poor objective and subjective health due to their chronic medical condition. Methods Cross-sectional study of 368 individuals with T2D (72 ± 4 years, 42% women), participating in the Israel Diabetes and Cognitive Decline Study. Personality was conceptualized using the five-factor model (agreeableness, conscientiousness, extraversion, neuroticism, openness). Objective health was operationalized by T2D-related clinical status, cognitive function, and motor ability. Subjective health was assessed using a single self-report question. Hayes' process macro was used for the moderation analyses. Results The objective-subjective health associations were stronger among individuals with increased neuroticism (proportion of days covered: p = 0.02; cognitive function: p = 0.003; hand grip: p = 0.02; 3-m walk: p = 0.04) as well as decreased openness (cognitive status: p = 0.04) and agreeableness (3-m walk: p = 0.02). Discussion Personality traits, and specifically neuroticism, can modify the associations between objective and subjective health in older adults with T2D. Findings contribute to the understanding of health as a multidimensional construct that encompasses medical and psychological aspects, especially among older adults with a chronic illness.

Objectives The APOE-e4 genotype has been associated with old-age depression, but this relationship has been rarely investigated in type 2 diabetes (T2D) older adults, who are at significantly increased risk for depression, a major contributor to T2D complications. We examined whether trajectories of depression symptoms over time differ by APOE-e4 genotype in older adults with T2D. Methods Participants [n=754 (13.1% APOE-e4 carriers)] were from the longitudinal Israel Diabetes and Cognitive Decline (IDCD) study. They were initially cognitively normal and underwent evaluations of depression approximately every 18 months using the 15-item version of the Geriatric Depression Scale (GDS) and the depression subscale of the Neuropsychiatric Inventory (NPI). APOE was defined as a dichotomy of e4 carriers and non-carriers. We used Hierarchical Linear Mixed Models (HLMM) that modeled the effects of APOE status on repeated GDS and NPI-depression scores in an unadjusted model (Model 1), adjusting for demographic factors (Model 2) and additionally adjusting for cardiovascular factors and global cognition (Model 3). Results Participants' mean age was 71.37 (SD=4.5); 38.2% female. In comparison to non-carriers, APOE-e4 carriers had lower mean GDS scores (β=-0.46, p=0.018) and lower NPI-depression scores (β=-0.170, p=0.038) throughout all study follow period. The groups did not differ in the slope of change over time in GDS (β=-0.005, p=0.252) or NPI-depression (β=-0.001, p=0.994) scores. Additional adjustment for cardiovascular factors and global cognition did not alter these results. Conclusions In older adults with T2D, APOE-e4 carriers have less depressive symptoms in successive measurements suggesting they may be less susceptible to depression. This article is protected by copyright. All rights reserved.

OBJECTIVE Depression is highly frequent in older adults with type 2 diabetes and is associated with cognitive impairment, yet little is known about how various depression dimensions differentially affect cognition. We investigated longitudinal associations of specific depression dimensions with cognitive decline. RESEARCH DESIGN AND METHODS Participants (N = 1,002) were from the Israel Diabetes and Cognitive Decline study, were ≥65 years of age, had type 2 diabetes, and were not experiencing dementia at baseline. Participants underwent a comprehensive neuropsychological battery at baseline and every 18 months thereafter, including domains of episodic memory, attention/working memory, semantic categorization/language, and executive function, and Z-scores of each domain were averaged and further normalized to calculate global cognition. Depression items from the 15-item Geriatric Depression Scale were measured at each visit and subcategorized into five dimensions: dysphoric mood, withdrawal-apathy-vigor (entitled apathy), anxiety, hopelessness, and memory complaint. Random coefficients models examined the association of depression dimensions with baseline and longitudinal cognitive functioning, adjusting for sociodemographics and baseline characteristics, including cardiovascular risk factors, physical activity, and use of diabetes medications. RESULTS In the fully adjusted model at baseline, all dimensions of depression, except for anxiety, were associated with some aspect of cognition (P values from 0.01 to 0.01). CONCLUSIONS Apathy was associated with a faster cognitive decline in executive function. These findings highlight the heterogeneity of depression as a clinical construct rather than as a single entity and point to apathy as a specific risk factor for cognitive decline among older adults with type 2 diabetes.

Background: Family history of Alzheimer’s disease (AD) is associated with increased dementia-risk. Objective: The Israel Registry for Alzheimer’s Prevention (IRAP) is a prospective longitudinal study of asymptomatic middle-aged offspring of AD patients (family history positive; FH+) and controls (whose parents have aged without dementia; FH–) aimed to unravel the contribution of midlife factors to future cognitive decline and dementia. Here we present the study design, methods, and baseline characteristics. Methods: Participants are members of the Maccabi Health Services, 40–65 years of age, with exquisitely detailed laboratory, medical diagnoses and medication data available in the Maccabi electronic medical records since 1998. Data collected through IRAP include genetic, sociodemographic, cognitive, brain imaging, lifestyle, and health-related characteristics at baseline and every three years thereafter. Results: Currently IRAP has 483 participants [mean age 54.95 (SD = 6.68) and 64.8% (n = 313) women], 379 (78.5%) FH+, and 104 (21.5%) FH–. Compared to FH–, FH+ participants were younger (p = 0.011), more often males (p = 0.003) and with a higher prevalence of the APOE E4 allele carriers (32.9% FH+, 22% FH–; p = 0.040). Adjusting for age, sex, and education, FH+ performed worse than FH–in global cognition (p = 0.027) and episodic memory (p = 0.022). Conclusion: Lower cognitive scores and higher rates of the APOE E4 allele carriers among the FH+ group suggest that FH ascertainment is good. The combination of long-term historical health-related data available through Maccabi with the multifactorial information collected through IRAP will potentially enable development of dementia-prevention strategies already in midlife, a critical period in terms of risk factor exposure and initiation of AD-neuropathology.

Older adults with type 2 diabetes (T2D) are at increased risk for depression, cognitive decline, and dementia compared to those without T2D. Little is known about the association of simultaneous changes in depression symptoms and cognitive decline over time.Subjects (n=1021; mean age 71.6 [SD=4.6]; 41.2% female) were initially cognitively normal participants of the Israel Diabetes and Cognitive Decline study who underwent evaluations of depression and cognition approximately every 18 months. Cognitive tests were summarized into four cognitive domains: episodic memory, attention/working memory, executive functions, and semantic categorization. The average of the z-scores of the four domains defined global cognition. Depression symptoms were assessed using the Geriatric Depression Scale, 15-item version. We fit a random coefficients model of changes in depression and in cognitive functions, adjusting for baseline sociodemographic and cardiovascular variables.Higher number of depression symptoms at baseline was significantly associated with lower baseline cognitive scores in global cognition (estimate = -0.1175, SE = 0.021, DF = 1,014, t = -5.59; p0.001), executive functions (estimate = -0.186, SE = 0.036, DF = 1,013, t = -5.15; p = 0.001), semantic categorization (estimate = -0.155, SE = 0.029, DF = 1,008, t = -5.3; p0.001), and episodic memory (estimate = -0.08165, SE = 0.027, DF = 1,035, t = -2.92; p = 0.0036), but not with rate of decline in any cognitive domain. During follow-up, a larger increase in number of depression symptoms, was associated with worse cognitive outcomes in global cognition (estimate = -0.1053, SE = 0.027, DF = 1,612, t = -3.77; p = 0.0002), semantic categorization (estimate = -0.123, SE = 0.036, DF = 1,583, t = -3.36; p = 0.0008), and in episodic memory (estimate = -0.165, SE = 0.055, DF = 1,622, t = -3.02; p = 0.003), but the size of this effect was constant over time.In elderly with T2D, increase in depression symptoms over time is associated with parallel cognitive decline, indicating that the natural course of the two conditions progresses concurrently and suggesting common underlying mechanisms".

First-degree family history is an established risk factor for Alzheimer's disease (AD). We investigated the association of late-onset AD risk loci with cognitive functioning among 315 offspring of AD patients. Participants were cognitively normal Jewish individuals, aged 40–65 years, from the Israel Registry for Alzheimer's Prevention (IRAP) study. Twenty-two single-nucleotide polymorphisms (SNPs) within these loci and the APOE E4 allele were included in the final analyses, and a polygenic risk score was also calculated. Using linear regression (assuming an additive genetic model), we found a significant association only for SNP rs9473117, located near the CD2-associated protein (CD2AP) gene, with global cognition. Controlling for demographic variables (age, sex, years of education, and ancestry), the late-onset AD risk allele C was associated with lower global cognitive functioning (p = 0.0005), and withstood correction for multiple testing. After adjusting for additional characteristics (APOE E4 status and then also for cardiovascular factors), the results remained essentially unchanged (p = 0.0003 and p = 0.0005, respectively). In secondary analyses examining specific cognitive domains, rs9473117 was similarly associated with episodic memory (p = 0.005), language (p = 0.009), and working memory/attention (p = 0.018) but not with executive functions (p = 0.27). Again, the results were similar after adjusting for APOE E4 status and cardiovascular factors. The polygenic risk score was not associated with global cognitive functioning or with any of the 4 domains. In conclusion, our findings suggest a contribution of the CD2AP locus to cognitive functioning in middle-aged individuals with a parental history of AD. Further validations, including in longitudinal studies, are required.

Type 2 diabetes (T2D) is associated with motor impairments and a higher dementia risk. The relationships of motor decline with cognitive decline in T2D older adults has rarely been studied. Using data from the Israel Diabetes and Cognitive Decline study (N = 892), we examined associations of decline in motor function with cognitive decline over a 54-month period.Motor function measures were strength (handgrip) and gait speed (time to walk 3 m). Participants completed a neuropsychologic battery of 13 tests transformed into z-scores, summarized into 4 cognitive domains: episodic memory, attention/working memory, executive functions, and language/semantic categorization. The average of the 4 domains' z-scores defined global cognition. Motor and cognitive functions were assessed in 18-months intervals. A random coefficients model delineated longitudinal relationships of cognitive decline with baseline and change from baseline in motor function, adjusting for sociodemographic, cardiovascular, and T2D-related covariates.Slower baseline gait speed levels were significantly associated with more rapid decline in global cognition (P = .004), language/semantic categorization (P = .006) and episodic memory (P = .029). Greater decline over time in gait speed was associated with an accelerated rate of decline in global cognition (P = .050), attention/working memory (P = .047) and language/semantic categorization (P.001). Baseline strength levels were not associated with cognitive decline but the rate of declining strength was associated with an accelerated decline in executive functions (P = .025) and language/semantic categorization (P = .006).In T2D older adults, the rate of decline in motor function, beyond baseline levels, was associated with accelerated cognitive decline, suggesting that cognitive and motor decline share common neuropathologic mechanisms in T2D.

Background High body mass index (BMI) is a risk factor for type 2 diabetes and cardiovascular disease. However, its relationships with indices of carotid stiffness and plaque volume are unclear. We investigated associations of long-term measurements of BMI with indices of carotid stiffness and atherosclerosis among non-demented diabetes patients from the Israel Diabetes and Cognitive Decline (IDCD) study.Methods Carotid ultrasound indices [carotid intima media thickness (cIMT), distensibility, elastography and plaque volume] were assessed in N = 471 participants. Mean BMI across all MHS diabetes registry measurements and trajectories of BMI were calculated. BMI was categorized into three trajectory groups representing: a relatively stable normal weight (n = 185, 44%), overweight trajectory (n = 188, 44.8%) and a trajectory of obesity (n = 47, 11.2%). Linear and logistic regressions estimated associations of carotid indices with mean BMI and BMI trajectories.Results Compared to the normal weight trajectory, an obesity trajectory was associated with carotid distensibility (β=-3.078, p = 0.037), cIMT (β = 0.095, p = 0.004), and carotid elastography (β = 0.181, p = 0.004) but not with plaque volume (β = 0.066, p = 0.858). Compared with the normal weight trajectory, an obesity trajectory was associated with increased odds for impaired carotid distensibility (OR = 2.790, p = 0.033), impaired cIMT (OR = 5.277, p = 0.001) and large carotid plaque volume (OR = 8.456, p = 0.013) but not with carotid elastography (OR = 1.956, p = 0.140). Mean BMI was linearly associated with Distensibility (β=-0.275, p = 0.005) and cIMT (β = 0.005, p = 0.026).Conclusions Long-term measurements of adiposity are associated with indices of carotid stiffness and plaque volume among older type 2 diabetes adults.

AIMS/HYPOTHESIS: There are established relationships between adiposity (obesity) and higher dementia risk, faster cognitive decline and associated neural injury. Type 2 diabetes is strongly linked to greater adiposity and has been consistently associated with neural injury and poor cognitive outcomes. However, although obesity is a major cause of type 2 diabetes, there is limited evidence on the association of adiposity with brain atrophy among individuals with type 2 diabetes. METHODS: We examined the association of BMI (a measure of adiposity), and of long-term trajectories of BMI (three empirically identified groups of trajectories—’normal’, ‘overweight’ and ‘obese’—using SAS macro PROC TRAJ), with regional brain volume, in a sample of older individuals (aged 64–84) with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline Study (n=198). RESULTS: Using linear regression, we found that greater BMI was associated with smaller volumes of the inferior frontal gyrus (IFG) (r=−0.25, p=0.001) and the middle temporal gyrus (r=−0.19; p=0.010) after adjusting for sociodemographic covariates and total intracranial volume. In addition, there were significant differences between BMI trajectory groups in IFG volume (F=4.34, p=0.014), such that a long-term trajectory of obesity was associated with a smaller volume. Additional adjustment for cardiovascular and diabetes-related potential confounders did not substantively alter the results. There were no associations of adiposity with superior frontal gyrus, middle frontal gyrus or total grey matter volumes. CONCLUSIONS/INTERPRETATION: In older adults with type 2 diabetes, long-term adiposity may have a detrimental impact on volume of brain regions relevant to cognitive functioning. Further studies to identify the underlying mechanisms are warranted.

Physical fitness is an important contributor to healthy aging that improves cognition. Older adults who engage in cardiorespiratory fitness activities show less cognitive decline.To examine whether physical fitness acts as a potential protective mechanism shielding against the negative associations between age and cognition. Specifically, we examined whether physical fitness mediates the relationship between age and processing speed.114 (M = 63.80, SD = 10.63) senior executives completed a computerized cognitive battery composed of four processing speed tasks. Level of physical fitness was assessed on a treadmill stress test and reported in metabolic equivalents (METs).Older age was associated with slower processing speed (r = 0.25, p = 0.007), whereas greater physical fitness was associated with faster processing speed (r = -0.30, p = 0.001). Path analysis indicated that the association between age and processing speed was fully mediated by the level of physical fitness (Indirect effect: β = 0.10, p = 0.008; Direct effect: β = 0.16, p = 0.20).The findings indicate that physical fitness is a strong mediator of the relationship between age and processing speed and imply that physical fitness makes a major contribution to cognitive reserve during the aging process. The results may suggest that the decrease in physical fitness during aging may partially account for slower cognitive processing.

Mild cognitive impairment (MCI) is a prodromal syndrome often linked to the eventual emergence of dementia syndromes such as Alzheimer’s disease (AD) and vascular dementia (VaD). Research regarding the potential treatment of MCI is reviewed. Current research suggests that neurocognitive decline associated with MCI that may evolve into a dementia syndrome is potentially managed by treating cardiovascular risk factors, appropriate diet and physical exercise, challenging mental activity, intervention for any neuropsychiatric issues, and encouraging meaningful psychosocial relationships. Recent research also suggests potentially better effect on neuropsychological functioning when medication such as donepezil is used to manage both dementia and MCI.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.