Prevention of Vascular Contributions to Cognitive Impairment and Dementia: The Role of Physical Activity and Exercise.

Vascular contributions to cognitive impairment and dementia, specifically cerebral small vessel disease (CSVD), are the second most common cause of dementia. Currently, there are no specific pharmacological treatments for CSVD, and the use of conventional antidementia drugs is not recommended. Exercise has the potential to prevent and mitigate CSVD-related brain damage and improve cognitive function. Mechanistic pathways underlying the neurocognitive benefits of exercise include the control of vascular risk factors, improving endothelial function, and upregulating exerkines. Notably, the therapeutic efficacy of exercise may vary by exercise type (ie, aerobic versus resistance training) and biological sex; thus, studies designed specifically to examine these moderating factors within a CSVD context are needed. Furthermore, future research should prioritize resistance training interventions, given their tremendous therapeutic potential. Addressing these knowledge gaps will help us refine exercise recommendations to maximize their therapeutic impact in the prevention and mitigation of CSVD.

Supporting physical activity for mobility in older adults with mobility limitations (SuPA Mobility): study protocol for a randomized controlled trial.

BACKGROUND: Limited mobility in older adults consistently predicts both morbidity and mortality. As individuals age, the rates of mobility disability increase from 1.0% in people aged 15-24 to 20.6% in adults over 65 years of age. Physical activity can effectively improve mobility in older adults, yet many older adults do not engage in sufficient physical activity. Evidence shows that increasing physical activity by 50 min of moderate intensity physical activity in sedentary older adults with mobility limitations can improve mobility and reduce the incidence of mobility disability. To maximize the healthy life span of older adults, it is necessary to find effective and efficient interventions that can be delivered widely to prevent mobility limitations, increase physical activity participation, and improve quality of life in older adults. We propose a randomized controlled trial to assess the effect of a physical activity health coaching intervention on mobility in older adults with mobility limitations. METHODS: This randomized controlled trial among 290 (145 per group) community-dwelling older adults with mobility limitations, aged 70-89 years old, will compare the effect of a physical activity health coaching intervention versus a general healthy aging education program on mobility, as assessed with the Short Physical Performance Battery. The physical activity health coaching intervention will be delivered by exercise individuals who are trained in Brief Action Planning. The coaches will use evidence-based behavior change techniques including goal-setting, action planning, self-monitoring, and feedback to improve participation in physical activity by a known dose of 50 min per week. There will be a total of 9 health coaching or education sessions delivered over 26 weeks with a subsequent 26-week follow-up period, wherein both groups will receive the same duration and frequency of study visits and activities. DISCUSSION: The consequences of limited mobility pose a significant burden on the quality of life of older adults. Our trial is novel in that it investigates implementing a dose of physical activity that is known to improve mobility in older adults utilizing a health coaching intervention. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System: NCT05978336; registered on 28 July 2023.

Aerobic exercise improves executive functions in females, but not males, without the BDNF Val66Met polymorphism.

BACKGROUND: Aerobic exercise promotes cognitive function in older adults; however, variability exists in the degree of benefit. The brain-derived neurotropic factor (BDNF) Val66Met polymorphism and biological sex are biological factors that have been proposed as important modifiers of exercise efficacy. Therefore, we assessed whether the effect of aerobic exercise on executive functions was dependent on the BDNFval66met genotype and biological sex. METHODS: We used data from a single-blind randomized controlled trial in older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Fifty-eight older adults were randomly assigned to either the 6 months, three times per week progressive aerobic training (AT) group or the usual care plus education control (CON) group. The secondary aim of the parent study included executive functions which were assessed with the Trail Making Test (B-A) and the Digit Symbol Substitution Test at baseline and trial completion at 6 months. RESULTS: Analysis of covariance, controlling for baseline global cognition and baseline executive functions performance (Trail Making Test or Digit Symbol Substitution Test), tested the three-way interaction between experimental group (AT, CON), BDNFval66met genotype (Val/Val carrier, Met carrier), and biological sex (female, male). Significant three-way interactions were found for the Trail Making Test (F(1,48) = 4.412, p < 0.04) and Digit Symbol Substitution Test (F(1,47) = 10.833, p < 0.002). Posthoc analyses showed female Val/Val carriers benefited the most from 6 months of AT compared with CON for Trail Making Test and Digit Symbol Substitution Test performance. Compared with CON, AT did not improve Trail Making Test performance in male Val/Val carriers or Digit Symbol Substitution Test performance in female Met carriers. CONCLUSIONS: These results suggest that future randomized controlled trials should take into consideration BDNF genotype and biological sex to better understand the beneficial effects of AT on cognitive function in vascular cognitive impairment to maximize the beneficial effects of exercise and help establish exercise as medicine for cognitive health.

Sex and BDNF Val66Met polymorphism matter for exercise-induced increase in neurogenesis and cognition in middle-aged mice.

Females show greater benefits of exercise on cognition in both humans and rodents, which may be related to brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP), the Val66Met polymorphism, within the human BDNF gene, causes impaired activity-dependent secretion of neuronal BDNF and impairments to some forms of memory. We evaluated whether sex and BDNF genotype (Val66Met polymorphism (Met/Met) versus wild-type (Val/Val)) influenced the ability of voluntary running to enhance cognition and hippocampal neurogenesis in mice. Middle-aged C57BL/6J (13 months) mice were randomly assigned to either a control or an aerobic training (AT) group (running disk access). Mice were trained on the visual discrimination and reversal paradigm in a touchscreen-based technology to evaluate cognitive flexibility. BDNF Met/Met mice had fewer correct responses compared to BDNF Val/Val mice on both cognitive tasks. Female BDNF Val/Val mice showed greater cognitive flexibility compared to male mice regardless of AT. Despite running less than BDNF Val/Val mice, AT improved performance in both cognitive tasks in BDNF Met/Met mice. AT increased neurogenesis in the ventral hippocampus of BDNF Val/Val mice of both sexes and increased the proportion of mature type 3 doublecortin-expressing cells in the dorsal hippocampus of female mice only. Our results indicate AT improved cognitive performance in BDNF Met/Met mice and increased hippocampal neurogenesis in BDNF Val/Val mice in middle age. Furthermore, middle-aged female mice may benefit more from AT than males in terms of neuroplasticity, an effect that was influenced by the BDNF Val66Met polymorphism.

Walking for Cognitive Health: Previous Parity Moderates the Relationship Between Self-Reported Walking and Cognition.

BACKGROUND: Older females show greater cognitive gains from physical activity (PA) than males, which may be related to long-term consequences of female-specific reproductive events (eg, pregnancy) on cognitive health. METHODS: To determine whether previous parity could moderate the relationship between PA and cognitive decline in older women, we conducted secondary analyses of data from the Health, Aging, and Body Composition Study. We tested whether the association between average PA over 10 years and cognition (Modified Mini-Mental State Examination [3MS]) and executive functioning (digit symbol substitution test [DSST]) over 10 years varied by previous parity (nulliparity, low parity, medium parity, and grand multiparity). An analysis of covariance was performed with cognition (average and change over 10 years) as the dependent variables, parity as a categorical predictor, average PA as a continuous predictor, and a set of relevant covariates. RESULTS: Significant interactions were found between PA and parity group for all 4 comparisons: average 3MS (p = .014), average DSST (p = .032), change in 3MS (p = .016), and change in DSST (p = .017). Simple slope analyses indicated the positive relationship between PA and average 3MS and DSST was only significant in the nulliparity and grand multiparity groups, and the positive relationship between PA and change in 3MS and DSST was only significant in the grand multiparity group. CONCLUSION: The findings suggest the relationship between self-reported walking and cognitive performance was strongest in the groups at risk for cognitive decline and dementia, the nulliparous and grand multiparous groups.

Reshaping the path of mild cognitive impairment by refining exercise prescription: a study protocol of a randomized controlled trial to understand the "what," "for whom," and "how" of exercise to promote cognitive function.

BACKGROUND: Targeted exercise training is a promising strategy for promoting cognitive function and preventing dementia in older age. Despite the utility of exercise as an intervention, variation still exists in exercise-induced cognitive gains and questions remain regarding the type of training (i.e., what), as well as moderators (i.e., for whom) and mechanisms (i.e., how) of benefit. Both aerobic training (AT) and resistance training (RT) enhance cognitive function in older adults without cognitive impairment; however, the vast majority of trials have focused exclusively on AT. Thus, more research is needed on RT, as well as on the combination of AT and RT, in older adults with mild cognitive impairment (MCI), a prodromal stage of dementia. Therefore, we aim to conduct a 6-month, 2 × 2 factorial randomized controlled trial in older adults with MCI to assess the individual effects of AT and RT, and the combined effect of AT and RT on cognitive function and to determine the possible underlying biological mechanisms. METHODS: Two hundred and sixteen community-dwelling adults, aged 65 to 85 years, with MCI from metropolitan Vancouver will be recruited to participate in this study. Randomization will be stratified by biological sex and participants will be randomly allocated to one of the four experimental groups: (1) 4×/week balance and tone (BAT; i.e., active control); (2) combined 2×/week AT + 2×/week RT; (3) 2×/week AT + 2×/week BAT; or (4) 2×/week RT + 2×/week BAT. The primary outcome is cognitive function as measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus. Secondary outcomes include cognitive function, health-related quality of life, physical function, actigraphy measures, questionnaires, and falls. Outcomes will be measured at baseline, 6 months (i.e., trial completion), and 18 months (i.e., 12-month follow-up). DISCUSSION: Establishing the efficacy of different types and combinations of exercise training to minimize cognitive decline will advance our ability to prescribe exercise as "medicine" to treat MCI and delay the onset and progression of dementia. This trial is extremely timely as cognitive impairment and dementia pose a growing threat to global public health. TRIAL REGISTRATION: ClinicalTrials.gov NCT02737878 . Registered on April 14, 2016.

Do the relationships of physical activity and total sleep time with cognitive function vary by age and biological sex? A cross-sectional analysis of the Canadian Longitudinal Study on Aging.

OBJECTIVES: Physical activity (PA) and total sleep time (TST) are each associated with cognition; however, whether these relationships vary by age and biological sex is unclear. We examined the relationships of PA or TST with cognition, and whether age and sex moderated these relationships, using baseline data from the Canadian Longitudinal Study on Aging (CLSA; 2010-2015). STUDY DESIGN: A cross-sectional analysis of participants from the Comprehensive cohort of the CLSA with complete PA and sleep data (n = 20,307; age range 45-86 years). MAIN OUTCOME MEASURES: PA and TST were measured using the Physical Activity Scale for the Elderly (PASE) and self-reported TST over the past month. Cognition was indexed using a three-factor structural equation model (i.e., memory, executive function, and verbal fluency). RESULTS: Non-linear restricted cubic spline models indicated that PA and TST explained statistically significant (p < 0.01) but modest variance of each cognitive domain (<1 % of 23-24 % variance). Age and sex did not moderate associations of PA with any cognitive domain. However, age and sex moderated relationships of TST with cognition, whereby: 1) associations of TST with memory decreased with age for males and females; and 2) males and females had different age-associated relationships of TST with executive function and verbal fluency. CONCLUSIONS: PA and TST modestly contribute to multiple domains of cognition across middle and older adulthood. Importantly, the association of PA with cognition does not appear to vary across middle or older adulthood, nor does it vary by biological sex; however, TST appears to have a complex relationship with multiple domains of cognition which is both age- and sex-dependent.

Effects of exercise training on the cognitive function of older adults with different types of dementia: a systematic review and meta-analysis.

OBJECTIVES: To assess the effect of exercise training on the cognitive function of older adults living with different types of dementia, as well as potential moderators of exercise efficacy. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Cochrane Central, PsycINFO, Embase, Medline and CINAHL. ELIGIBILITY CRITERIA: Peer-reviewed, randomised controlled trials, in English (1990-present), which examined the effects of exercise training on the cognitive function of older adults living with dementia. STUDY APPRAISAL AND SYNTHESIS: Risk of bias and study quality were assessed (Cochrane Risk of Bias Tool 2.0 and Physiotherapy Evidence Database Scale). We performed random-effects models using robust variance estimation and tested moderators using the approximate Hotelling-Zhang test. RESULTS: Twenty-eight studies (n=2158) were included in the qualitative review and 25 in the meta-analysis. For all-cause dementia, a small effect of exercise training on cognitive function was observed (g=0.19; 95% CI 0.05 to 0.33; p=0.009). Type of dementia and exercise training characteristics did not moderate the effects of exercise training on cognitive function (p>0.05). Adherence to the intervention moderated the cognitive outcome effect size such that greater mean adherence was associated with greater cognitive outcome effect sizes (b=0.02; SE=0.01; p=0.005). CONCLUSION: Exercise training showed small benefits for the cognitive function of older adults living with all-cause dementia. More research and standardised reporting of exercise training characteristics can strengthen the evidence for what works best for which types of dementia. PROSPERO REGISTRATION NUMBER: CRD42020198716.

Sex Differences in the Relationship Between Arterial Stiffness and Cognitive Function in Older Adults.

OBJECTIVE: To examine potential sex differences in the relationship between arterial stiffness and global cognitive function and executive functions. METHODS: Baseline data from 80 older adults were included from two randomized controlled trials (NCT02669394 and NCT02737878). Arterial stiffness was measured by carotid-femoral pulse wave velocity (cf-PWV). Cognitive function assessment included global cognition (Mini-Mental State Examination [MMSE]) and executive functions (set shifting [Trail Making Test Part B minus A], inhibition [Stroop Test], and working memory [Verbal Digit Span Backwards Test]). Separate statistical models were constructed to assess the effect of cf-PWV on each cognitive outcome for females and males. Each statistical model controlled for Framingham cardiovascular disease risk score and education. RESULTS: Higher cf-PWV was associated with impaired MMSE performance in males (ß = -0.48; p = 0.018), but not females (p ≥ 0.389). For executive processes, higher cf-PWV was associated with impaired Trail Making Test Part B minus A (ß = 0.56; p = 0.005) and Stroop Test (ß = 0.59; p = 0.004) in males, but not in females (ps ≥ 0.108). cf-PWV was not significantly associated with Verbal Digit Span Forward minus Backward Test in males or females (ps ≥ 0.108). CONCLUSIONS: Arterial stiffness is more strongly associated with cognitive impairment in males than females. These results further elucidate the interplay between vascular health and cognitive function by providing support for sex-specific mechanisms.

Sex Differences in Subsequent Falls and Falls Risk: A Prospective Cohort Study in Older Adults.

BACKGROUND: Sex differences for subsequent falls and falls risk factors in community-dwelling older adults who have fallen are unknown. Our aim was to: (1) compare the number of falls between sexes, (2) identify modifiable falls risk factors, and (3) explore the interaction of sex on falls risk factors in older adults who fall. METHODS: Four hundred sixty-two community dwellers seeking medical attention after an index fall were recruited from the Vancouver Falls Prevention Clinic and participated in this 12-month prospective cohort study. Ninety-six participants were part of a randomized controlled trial of exercise. Falls were tracked with monthly falls calendars. Demographics, falls risk measures, and the number of subsequent falls were compared between sexes. A principal component analysis (PCA) was employed to reduce the falls risk measures to a smaller set of factors. The PCA factors were used in negative binomial regression models to predict the number of subsequent falls. Age, exposure time (i.e., number of falls monitoring days), and prescribed exercise (yes/no) were used as covariates, and sex (male/female) and PCA factors were used as main effects. The interaction of sex by PCA factor was then included. RESULTS: Males fell more over 12 months (males: 2.80 ± 6.86 falls; females: 1.25 ± 2.63 falls) than females, and poorer executive function predicted falls in males. Four PCA factors were defined - impaired cognition and mobility, low mood and self-efficacy, mobility resilience, and perceived poor health - each predicted the number of falls. The sex by mobility resilience interaction suggested that mobility resilience was less protective of falls in males. CONCLUSION: Modifiable risk factors related to cognition, physical function, psychological wellbeing, and health status predicted subsequent falls. In males, better mobility was not as protective of falls compared with females. This may be due to males' poorer executive function, contributing to decreased judgement or slowed decision-making during mobility. These results may inform efficacious sex-specific falls prevention strategies.

Are sex differences in cognitive impairment reflected in epigenetic age acceleration metrics?

Sex differences are well-established in Alzheimer's disease (AD) frequency and pathogenesis, but are not mechanistically understood. Accelerated epigenetic age has been associated with both cognitive aging and AD pathophysiology, but has not been studied by sex in AD or related cognitive impairment. Using the ADNI cohort, we found that none of sex, cognitive impairment diagnosis, nor load of APOEε4 alleles (strongest genetic AD risk factor) were associated with epigenetic age acceleration (DNAmAge, Intrinsic DNAmAge, PhenoAge, or GrimAge), although females exhibit more accelerated epigenetic aging using the Skin & Blood clock in the transition from normal cognition to cognitive impairment than males.

Cardiometabolic risk, biological sex, and age do not share an interactive relationship with cognitive function: a cross-sectional analysis of the Canadian Longitudinal Study on Aging.

It is unclear whether cardiometabolic risk shares an interactive relationship with age-associated differences in cognition, and whether this relationship varies by biological sex. We conducted a cross-sectional analysis using baseline data from the Canadian Longitudinal Study on Aging (CLSA; 2010-2015) to examine whether 1) cardiometabolic risk has an interactive relationship with age-associated cognition; and 2) interactive effects are sex-dependent. We measured memory, executive function, and verbal fluency in the Comprehensive cohort (N = 25 830; 45-86 years). Each cognitive domain was modeled using restricted cubic splines for age and each cardiometabolic risk factor (HbA1c, HSCRP, TG, and LDL and HDL cholesterol). Sex was included as a predictor in all models. Wald χ2 statistics were used to determine the relative importance of age, cardiometabolic risk, sex, and their interactive effects on cognition. Age was the most important variable in each model (proportion χ2 = 34%-48%). Biological sex was the second most important variable for memory (proportion χ2 = 26%) but was unimportant for executive function and verbal fluency (proportion χ2 = 3%-5%). Cardiometabolic risk factors were unimportant predictors in each model (proportion χ2 = 1%-3%). Two- and 3-way interactions between cardiometabolic risk, age, and sex were also unimportant (proportion χ2 = 0%-2%). Thus, cardiometabolic risk factors did not meaningfully account for age-associated differences in cognition, and these associations (or lack thereof) did not vary by sex. Novelty: Males have poorer age-associated cognitive performance than females. Females and males differ in cardiometabolic risk across middle and older adulthood. Cardiometabolic risk has a small association with age-associated cognition, and there are no sex differences in this relationship.

Cardiovascular risk moderates the effect of aerobic exercise on executive functions in older adults with subcortical ischemic vascular cognitive impairment.

Aerobic training (AT) can promote cognitive function in adults with Subcortical Ischemic Vascular Cognitive Impairment (SIVCI) by modifying cardiovascular risk factors. However, pre-existing cardiovascular health may attenuate the benefits of AT on cognitive outcomes in SIVCI. We examined whether baseline cardiovascular risk moderates the effect of a 6-month progressive AT program on executive functions with a secondary analysis of a randomized controlled trial in 71 adults, who were randomized to either: (1) 3×/week progressive AT; or (2) education program (CON). Three executive processes were measured: (1) response inhibition by Stroop Test; (2) working memory by digits backward test; and (3) set shifting by the Trail Making Test. Baseline cardiovascular risk was calculated using the Framingham cardiovascular disease (CVD) Risk Score (FCRS), and participants were classified as either low risk (< 20% FCRS score; LCVR) or high risk (≥ 20% FCRS score; HCVR). A complete case analysis (n = 58) was conducted using an analysis of covariance (ANCOVA) to evaluate between-group differences in the three executive processes. A significant interaction was found between cardiovascular risk group and intervention group (AT or CON) for the digit span backward and the Trail Making Test. AT improved performance compared with CON in those with LCVR, while in those with HCVR, AT did not improve performance compared with CON. Baseline cardiovascular risk significantly moderates the efficacy of AT on cognition. Our findings highlight the importance of intervening early in the disease course of SIVCI, when cardiovascular risk may be lower, to reap maximum benefits of aerobic exercise.

Sex influences the effects of APOE genotype and Alzheimer's diagnosis on neuropathology and memory.

Alzheimer's disease (AD) is characterized by severe cognitive decline and pathological changes in the brain (brain atrophy, hyperphosphorylation of tau, and deposition of amyloid-beta protein). Females have greater neuropathology (AD biomarkers and brain atrophy rates) and cognitive decline than males, however these effects can depend on diagnosis (amnestic mild cognitive impairment (aMCI) or AD) and APOE genotype (presence of ε4 alleles). Using the ADNI database (N = 630 females, N = 830 males), we analyzed the effect of sex, APOE genotype (non-carriers or carriers of APOEε4 alleles), and diagnosis (cognitively normal (CN), early aMCI (EMCI), late aMCI (LMCI), probable AD) on cognition (memory and executive function), hippocampal volume, and AD biomarkers (CSF levels of amyloid beta, tau, and ptau). Regardless of APOE genotype, memory scores were higher in CN, EMCI, and LMCI females compared to males but this sex difference was absent in probable AD, which may suggest a delay in the onset of cognitive decline or diagnosis and/or a faster trajectory of cognitive decline in females. We found that, regardless of diagnosis, CSF tau-pathology was disproportionately elevated in female carriers of APOEε4 alleles compared to males. In contrast, male carriers of APOEε4 alleles had reduced levels of CSF amyloid beta compared to females, irrespective of diagnosis. We also detected sex differences in hippocampal volume but the direction was dependent on the method of correction. Altogether results suggest that across diagnosis females show greater memory decline compared to males and APOE genotype affects AD neuropathology differently in males and females which may influence sex differences in incidence and progression of aMCI and AD.

Reshaping the path of vascular cognitive impairment with resistance training: a study protocol for a randomized controlled trial.

BACKGROUND: Subcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. Importantly, SIVCI is considered the most treatable form of cognitive impairment in older adults, due to its modifiable risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia. Exercise training is a promising intervention to delay the progression of SIVCI, as it actively targets these cardiometabolic risk factors. Despite the demonstrated benefits of resistance training on cognitive function and emerging evidence suggesting resistance training may reduce the progression of white matter hyperintensities (WMHs), research on SIVCI has predominantly focused on the use of aerobic exercise. Thus, the primary aim of this proof-of-concept randomized controlled trial is to investigate the efficacy of a 12-month, twice-weekly progressive resistance training program on cognitive function and WMH progression in adults with SIVCI. We will also assess the efficiency of the intervention. METHODS: Eighty-eight community-dwelling adults, aged > 55 years, with SIVCI from metropolitan Vancouver will be recruited to participate in this study. SIVCI will be determined by the presence of cognitive impairment (Montreal Cognitive Assessment < 26) and cerebral small vessel disease using computed tomography or magnetic resonance imaging. Participants will be randomly allocated to a twice-weekly exercise program of (1) progressive resistance training or (2) balance and tone training (i.e., active control). The primary outcomes are cognitive function measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-13 with additional cognitive tests) and WMH progression. DISCUSSION: The burden of SIVCI is immense, and to our knowledge, this will be the first study to quantify the effect of progressive resistance training on cognitive function and WMH progression among adults with SIVCI. Slowing the rate of cognitive decline and WMH progression could preserve functional independence and quality of life. This could lead to reduced health care costs and avoidance of early institutional care. TRIAL REGISTRATION: ClinicalTrials.gov NCT02669394 . Registered on February 1, 2016.

Exploring the Contribution of Myelin Content in Normal Appearing White Matter to Cognitive Outcomes in Cerebral Small Vessel Disease.

BACKGROUND: Myelin damage is a salient feature in cerebral small vessel disease (cSVD). Of note, myelin damage extends into the normal appearing white matter (NAWM). Currently, the specific role of myelin content in cognition is poorly understood. OBJECTIVE: The objective of this exploratory study was to investigate the association between NAWM myelin and cognitive function in older adults with cSVD. METHODS: This exploratory study included 55 participants with cSVD. NAWM myelin was measured using myelin water imaging and was quantified as myelin water fraction (MWF). Assessment of cognitive function included processing speed (Trail Making Test Part A), set shifting (Trail Making Test Part B minus A), working memory (Verbal Digit Span Backwards Test), and inhibition (Stroop Test). Multiple linear regression analyses assessed the contribution of NAWM MWF on cognitive outcomes controlling for age, education, and total white matter hyperintensity volume. The overall alpha was set at ≤0.05. RESULTS: After accounting for age, education, and total white matter hyperintensity volume, lower NAWM MWF was significantly associated with slower processing speed (ß â€Š= -0.29, p = 0.037) and poorer working memory (ß= 0.30, p = 0.048). NAWM MWF was not significantly associated with set shifting or inhibitory control (p > 0.132). CONCLUSION: Myelin loss in NAWM may play a role in the evolution of impaired processing speed and working memory in people with cSVD. Future studies, with a longitudinal design and larger sample sizes, are needed to fully elucidate the role of myelin as a potential biomarker for cognitive function.

Inflammation in Alzheimer's Disease: Do Sex and APOE Matter?

BACKGROUND: Alzheimer's disease (AD) disproportionately affects females with steeper cognitive decline and more neuropathology compared to males, which is exacerbated in females carrying the APOEɛ4 allele. The risk of developing AD is also higher in female APOEɛ4 carriers in earlier age groups (aged 65-75), and the progression from cognitively normal to mild cognitive impairment (MCI) and to AD may be influenced by sex. Inflammation is observed in AD and is related to aging, stress, and neuroplasticity, and although studies are scarce, sex differences are noted in inflammation. OBJECTIVE: The objective of this study was to investigate underlying physiological inflammatory mechanisms that may help explain why there are sex differences in AD and APOEɛ4 carriers. METHODS: We investigated, using the ADNI database, the effect of sex and APOE genotype (non-carriers or carriers of 1 and 2 APOEɛ4 alleles) and sex and diagnosis (cognitively normal (CN), MCI, AD) on CSF (N = 279) and plasma (N = 527) markers of stress and inflammation. RESULTS: We found CSF IL-16 and IL-8 levels differed by sex and APOE genotype, as IL-16 was higher in female APOEɛ4 carriers compared to non-carriers, while the opposite pattern was observed in males with IL-8. Furthermore, females had on average higher levels of plasma CRP and ICAM1 but lower levels of CSF ICAM1, IL-8, IL-16, and IgA than males. Carrying APOEɛ4 alleles and diagnosis (MCI and AD) decreased plasma CRP in both sexes. CONCLUSION: Sex and APOE genotype differences in CSF and plasma inflammatory biomarkers support that the underlying physiological changes during aging differ by sex and tissue origin.