Cognitive reserve (CR) has been linked to dementia, yet its influence on the risk of depression and related outcomes remains unknown. We aimed to examine the association of CR with depression and subsequent dementia or death, and to assess the extent to which CR is related to depression-free survival.

Within the UK Biobank, 436,232 participants free of depression and dementia were followed. A comprehensive CR indicator (low, moderate, and high) was created using latent class analysis based on information on education, occupation, mentally passive sedentary behavior, social connection, confiding with others, and leisure activities. Depression, dementia, and survival status were ascertained through self-reported medical history and/or linkages to medical records. Data were analyzed using multi-state Markov model and Laplace regression.

Over a median follow-up of 12.96 years, 16,560 individuals developed depression (including 617 with subsequent dementia) and 28,655 died. In multivariable multi-state models, compared with low CR, high CR was associated with lower risk of depression (hazard ratio 0.53 [95% confidence interval 0.51–0.56]) and lower risk of post-depression dementia (0.55 [0.34–0.88]) or death (0.69 [0.55–0.88]) in middle-aged adults (aged <60 years). In Laplace regression, the depression-free survival time was prolonged by 2.77 (2.58–2.96) years in participants with high compared to low CR.

High CR is associated with lower risks of depression and subsequent transitions to dementia and death, particularly in middle age. High CR may prolong depression-free survival. Our findings highlight the importance of enhancing CR in the prevention and prognosis of depression.

It remains unclear whether cognitive reserve can attenuate dementia risk among people with different genetic predispositions.

We aimed to examine the association between cognitive reserve and dementia, and further to explore whether and to what extent cognitive reserve may modify the risk effect of genetic factors on dementia.

Within the UK Biobank, 210 631 dementia-free participants aged ≥60 years were followed to detect incident dementia. Dementia was ascertained through medical and death records. A composite cognitive reserve indicator encompassing education, occupation and multiple cognitively loaded activities was created using latent class analysis, categorised as low, moderate and high level. Polygenic risk scores for Alzheimer's disease were constructed to evaluate genetic risk for dementia, categorised by tertiles (high, moderate and low). Data were analysed using Cox models and Laplace regression.

In multi-adjusted Cox models, the hazard ratio (HR) of dementia was 0.66 (95% confidence interval (CI) 0.61–0.70) for high cognitive reserve compared with low cognitive reserve. In Laplace regression, participants with high cognitive reserve developed dementia 1.62 (95% CI 1.35–1.88) years later than those with low cognitive reserve. In stratified analysis by genetic risk, high cognitive reserve was related to more than 30% lower dementia risk compared with low cognitive reserve in each stratum. There was an additive interaction between low cognitive reserve and high genetic risk on dementia (attributable proportion 0.24, 95% CI 0.17–0.31).

High cognitive reserve is associated with reduced risk of dementia and may delay dementia onset. Genetic risk for dementia may be mitigated by high cognitive reserve. Our findings underscore the importance of enhancing cognitive reserve in dementia prevention.

Cognitive Reserve (CR) developed from observation that several individuals show fewer cognitive impairment compared to others with the same brain injuries or neuropathology. Cognitive reserve is a potentially modifiable characteristic. Most of studies on cognitive reserve were conducted on chronic progressive diseases such as dementia. This study aims to define the role of cognitive reserve in geriatric delirium cases.

This case-control study was conducted in the acute geriatric inpatient of Cipto Mangunkusumo Hospital, Jakarta, Indonesia on June to September 2019 that consisted of 33 subjects with delirium and 33 controls. The measurement of cognitive reserve was done using the Indonesian adaptation of Cognitive Reserve Index questionnaire (CRIq) with 3 subscales, i.e. Education, Work Activity and Leisure Time.

We found that the CRIq scores of delirium patients were lower compared to the non-delirium controls both on total and each subscores, with a statistically significant mean difference (p<0,01). Patients with low-medium cognitive reserve also more likely to develop delirium compared to those with medium-high cognitive reserve (OR 9; 95% CI 2.86 to 28.22).

Low cognitive reserve may serve as a risk factor for delirium in the elderly. The measure of CRI in the geriatric inpatients unit can be used to determine those at risk of developing delirium. Further research are warranted to elaborate potentially modifiable variables of cognitive reserve to minimize the risk of delirium.

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive decline in motor function in all patients and cognitive impairment in a subset of patients. Evidence suggests that cognitive reserve (CR) may protect against cognitive and motor decline in ALS, but less is known about the impact of specific occupational skills and requirements on clinical outcomes in ALS. We expected that a history of working jobs with more complex cognitive demands would protect against cognitive decline, while jobs that require fine and complex motor skills would protect against motor dysfunction.

Participants were 150 ALS patients recruited from the University of Pennsylvania’s Comprehensive ALS Center. Participants underwent clinical and neuropsychological evaluations within 1 year of ALS diagnosis. Cognitive performance was measured using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), which includes ALS-Specific (e.g., verbal fluency, executive functions, language, social cognition) and NonSpecific (e.g., memory, visuospatial functions) composite scores. Motor functioning was measured using the Penn Upper Motor Neuron (UMN) scale and the ALS Functional Rating Scale (ALS-FRS). Occupational skills and requirements for each participant were assessed using data from the Occupational Information Network (O*NET) Database. O*NET data were assessed using principal components analysis, and 17 factor scores were derived representing distinct worker characteristics (n=5), occupational requirements (n=7), and worker requirements (n=5). These scores were entered as independent variables in multiple linear regression models using ECAS, UMN, and ALS-FRS scores as dependent variables covarying for education.

Preserved ECAS ALS-Specific performance was associated with jobs that involve greater reasoning abilities (ß=2.03, S.E.=0.79, p<.05), analytic skills (ß=3.08, S.E.=0.91, p<.001), and humanities knowledge (ß=1.20, S.E.=0.58, p<.05), as well as less exposure to environmental hazards (ß=-2.42, S.E.=0.76, p<.01) and fewer demands on visualperceptual (ß=-1.75, S.E.=0.73, p<.05) and technical skills (ß=-1.62, S.E.=0.63, p<.05). Preserved ECAS Non-Specific performance was associated with jobs that involve greater exposure to conflict (ß=0.82, S.E.=0.33, p<.05) and social abilities (ß=0.65, S.E.=0.29, p<.05). Jobs involving greater precision skills (ß=1.92, S.E.=0.79, p<.05) and reasoning ability (ß=2.10, S.E.=0.95, p<.05) were associated with greater disease severity on the UMN, while jobs involving more health services knowledge were associated with worse motor functioning on the ALS-FRS (ß=-1.30, S.E.=0.60, p<.05).

Specific occupational skills and requirements show protective effects on cognitive functioning in ALS, while others confer risk for cognitive and motor dysfunction. Preserved cognitive functioning was linked to a history of employment in jobs requiring strong reasoning abilities, social skills, and humanities knowledge, while poorer cognitive functioning was linked to jobs involving a high risk of exposure to environmental hazards and high visuo-perceptual and technical demands. In contrast, we did not find evidence of motor reserve, as no protective effects of occupational skills and requirements were found for motor symptoms, and jobs involving greater precision skills, reasoning abilities, and health services knowledge were linked to worse motor functioning. Our findings offer new insights into how occupational history may protect against cognitive impairment or confer elevated risk for cognitive and motor dysfunction in ALS.

Cognitive reserve and health-related fitness are associated with favorable cognitive aging, but Black/African American older adults are underrepresented in extant research. Our objective was to explore the relative contributions and predictive value of cognitive reserve and health-related fitness metrics on cognitive performance at baseline and cognitive status at a 4-year follow up in a large sample of Black/African American older adults.

Participants aged 65 years and older from the Health and Retirement Study (HRS) who identified as Black/African American and completed baseline and follow-up interviews (including physical, health, and cognitive assessments) were included in the study. The final sample included 321 Black/African American older adults (mean age = 72.8; sd = 4.8; mean years of education = 12.3; sd = 2.9; mean body mass index (BMI) = 29.1; sd = 5.2; 60.4% identified as female). A cross-sectional analysis of relative importance – a measure of partitioned variance controlling for collinearity and model order – was first used to explore predictor variables and inform the hierarchical model order. Next, hierarchical multiple regression was used to examine cross-sectional relationships between cognitive reserve (years of education), health-related fitness variables (grip strength, lung capacity, gait speed, BMI), and global cognition. Multiple logistic regression was used to examine prospective relationships between predictors and longitudinal cognitive status (maintainers versus decliners). Control variables in all models included age, gender identity, and a chronic disease index score.

Cross-sectional relative importance analyses identified years of education and gait speed as important predictors of global cognition. The cross-sectional hierarchical regression model explained 33% of variance in baseline global cognition. Education was the strongest predictor of cognitive performance (β = 0.48, p < 0.001). Holding all other variables constant, gait speed was significantly associated with baseline cognitive performance and accounted for a significant additional amount of explained variance (ΔR = 0.01, p = 0.032). In a prospective analysis dividing the sample into cognitive maintainers and decliners, a single additional year of formal education increased chances of being classified as a cognitive maintainer (OR = 1.30, 95% CI = 1.17-1.45). There were no significant relationships between rate of change in health-related fitness and rate of change in cognition.

Education, a proxy for cognitive reserve, was a robust predictor of global cognition at baseline and was associated with increased odds of maintaining cognitive ability at 4-year follow up in Black/African American older adults. Of the physical performance metrics, gait speed was associated with cognitive performance at baseline. The lack of observed association between other fitness variables and cognition may be attributable to the brief assessment procedures implemented in this large-scale study.

Individuals with Parkinson's disease (PD) have varying trajectories of cognitive decline. One reason for this heterogeneity may be "cognitive reserve": where higher education/IQ/current mental engagement compensates for increasing brain burden (Stern et al., 2020). With few exceptions, most studies examining cognitive reserve in PD fail to include brain metrics. This study's goal was to examine whether cognitive reserve moderated the relationship between neuroimaging indices of brain burden (diffusion free water fraction and T2-weighted white matter changes) and two commonly impaired domains in PD: executive function and memory. We hypothesized cognitive reserve would mitigate the relationship between higher brain burden and worse cognitive performance.

Participants included 108 individuals with PD without dementia (age mean=67.9±6.3, education mean=16.6±2.5) who were prospectively recruited for two NIH-funded projects at the University of Florida. All received neuropsychological measures of executive function (Trails B, Stroop, Letter Fluency) and memory (delayed recall: Hopkin's Verbal Learning Test-Revised, WMS-III Logical Memory). Domain specific z-score composites were created using data from age/education matched non-PD peer controls (N=62). For the Cognitive Reserve (CR) proxy, a z-score composite included years of education, WASI-II Vocabulary, and Wechsler Test of Adult Reading. At the time of testing, participants completed multiple MRI scans (T1-weighted, diffusion, Fluid Attenuated Inversion Recovery) from which the following were extracted: 1) whole-brain free water within the white matter (a measure of microstructural integrity and neuroinflammation), 2) white matter hyperintensities/white matter total volume (WMH/WMV), and bilaterally-averaged edge weights of white matter connectivity between 3) dorsolateral prefrontal cortex and caudate and 4) entorhinal cortex and hippocampi. Separate linear regressions for each brain metric used executive function and memory composites as dependent variables; predictors were age, CR proxy, respective brain metric, and a residual centered interaction term (brain metric*CR proxy). Identical models were run in dichotomized short and long disease duration groups (median split=6 years).

In all models, a lower CR proxy significantly predicted worse executive function (WMH/WMV: beta=0.49, free water: beta=0.54, frontal edge weight: beta=0.49, p's<0.001) and memory (WMH/WMV: beta=0.42, free water: beta=0.35, temporal edge weight: beta=0.39, p's <0.01). For neuroimaging metrics, higher free water significantly predicted worse executive function (beta=-0.39, p=0.002) but not memory. No other brain metrics were significant predictors of either domain. Accounting for PD duration, higher free water predicted worse executive function for those with both short (beta=-0.49, p=0.04) and long disease duration (beta=-0.48, p=0.02). Specifically in those with long disease duration, higher free water (beta=-0.57 p=0.02) and lower edge weights between entorhinal cortex and hippocampi (beta=0.30, p=0.03) predicted worse memory. Overall, no models contained significant interactions between the CR proxy and any brain metric.

Results replicate previous work showing that a cognitive reserve proxy relates to cognition. However, cognitive reserve did not moderate brain burden's relationship to cognition. Across the sample, greater neuroinflammation was associated with worse executive function. For those with longer disease duration, higher neuroinflammation and lower medial temporal white matter connectivity related to worse memory. Future work should examine other brain burden metrics to determine whether/how cognitive reserve influences the cognitive trajectory of PD.

Higher educational attainment is associated with reduced risk for Alzheimer's disease (AD) dementia, and its protective effect may act through alterations in cerebral blood flow (CBF) that allow for better coping with accumulating neuropathology. Additionally, there are sex differences in both the risk of developing AD as well as the potential protective effects of education. We therefore sought to investigate whether education moderates the association of hippocampal CBF and memory in cognitively unimpaired older adults, and to examine if these interactions were moderated by sex.

Cognitively unimpaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 51 men, 50 women) underwent neuropsychological evaluation and arterial spin labeling MRI, which was used to quantify bilateral hippocampal CBF. Sex was defined as sex at birth. Multiple linear regressions assessed (1) the independent associations among education, CBF, and memory performance separately in men and women and (2) the three-way interactions among CBF, sex, and education, followed by sex-stratified analyses. Three outcome measures were examined: Logical Memory Story A immediate and delayed recall, and Rey Auditory Verbal Learning Test (RAVLT) intrusions. All models adjusted for age and APOE epsilon-4 allele frequency, and all models with CBF additionally adjusted for cerebral metabolism (baseline FDG-PET composite) and pulse pressure.

CBF was not associated with education or memory in either women or men. There was a positive association between education and delayed memory in women (ß=0.14, t=2.64, p=0.008) as well as trending, positive associations between education and immediate memory in women (ß=0.09, t=1.79, p=0.074) and education and delayed memory in men (ß=0.09, t=1.94, p=0.054). Three-way interactions among sex, CBF, and education were significant on immediate recall (ß=2.55, t=2.53, p=0.013), delayed recall (ß=2.56, t=2.44, p=0.017), and RAVLT intrusions (ß=-2.28, t=-2.27, p=0.026). In women, there were interactions between education and hippocampal CBF on both immediate (ß=2.49, t=2.90, p=0.006) and delayed recall (ß=2.30, t=2.78, p=0.009), such that as education increased, the strength of the association between CBF and immediate memory increased. There was also an interaction between education and hippocampal CBF on RAVLT intrusions in women (ß=-2.42, t=-3.05, p=0.004), such that as education increased, the strength of the association between CBF and number of intrusions decreased; there was a main effect where in women with lower education, as CBF increased, the number of intrusions increased (ß=0.76, t=2.59, p=0.032); in women with higher education, there was no association between CBF and intrusions. In men, none of these two-way interactions were significant.

These results suggest that, in cognitively unimpaired older women, the relationship between hippocampal CBF and memory is moderated by education level, even when adjusting for several other factors. Specifically, higher education may serve as a protective factor in the hippocampal CBF-memory relationship, and this relationship was sex-dependent, occurring in women only. Further research is needed to examine these relationships longitudinally across the clinical continuum of AD. Additionally, this work needs to be conducted in more diverse samples to allow for analyses investigating the impact of education on the intersection of race/ethnicity and sex/gender.

Cognitive reserve has been linked to functional ability, and depression has been shown to be associated with more functional impairment in older adults. While cognitive reserve and depression are associated and have each been shown to impact functional impairment, the independent impact of cognitive reserve on functional ability after accounting for depressive symptoms has not been explored. For the purpose of this study, years of education served as a proxy for cognitive reserve, which is consistent with the literature. It was predicted that higher levels of education would be associated with better functional ability regardless of age and severity of depressive symptoms.

Participants (ages 55 to 90) were drawn from the Alzheimer’s Disease Neuroimaging Initiative (N=3407); participants with major depression were not included. Subsyndromal depressive symptoms were measured using the Geriatric Depression Scale (GDS < 6) and functional impairment was assessed using the Functional Activities questionnaire. A three-stage hierarchical regression was conducted with functional ability as the dependent variable.

Age, entered at stage one of the regression model, was a significant predictor (F(1,1427) =49.75, p<.001) and accounted for 3.4% of the variance in functional ability. Adding depressive symptoms to the regression model led to a significant increase in variance explained (F(1,1426) = 64.57, p<.001), accounting for an additional 4.2% of the variance in functional ability. Adding years of education to the regression model explained an additional 1.4% of variance in functional ability and this increase in variance explained was significant (F(1,1425) = 22.53, p<.001).

Cognitive reserve (operationalized as higher levels of education) was associated with higher functional ability even after accounting for age and depressive symptoms.

The concept of cognitive reserve (CR) explains why individuals with higher education, intelligence, or occupational attainment exhibit less severe cognitive changes in the presence of age-related or neurodegenerative pathology. CR may be a useful construct in understanding the cognitive performance of patients with late life depression (LLD), a cohort who are twice as likely to later receive a clinical diagnosis of dementia. It follows that depressed older adults with low CR may be at greater risk of cognitive decline compared to non-depressed older adults matched for CR. However, the literature on CR and LLD is limited to cross-sectional studies with mixed findings as to whether proxies of CR moderate cognitive outcomes in LLD. For example, both higher and lower education levels in LLD are associated with greater cognitive impairment in LLD compared to similarly educated non-depressed older adults. Longitudinal studies may help disentangle the association between CR and cognitive outcomes in LLD. The current study investigated the interaction between proxies of CR (e.g., education) and depression status on cognitive functioning over three years. We hypothesized that depressed older adults with low CR would demonstrate greater cognitive impairment and decline compared to depressed elders with high CR and non-depressed older adults with comparable CR.

Older adults with LLD and non-depressed older adults age 59+ participated. All participants were free of dementia at baseline. We divided both patients and non-depressed participants into low (<16) and high (>=16) education groups based upon the median years of education (16) of the entire sample. All participants underwent detailed neuropsychological testing. Composite measures of episodic memory (CERAD Wordlist and recall, LM I and LM II, BVRT), processing speed-executive functioning (SDMT and Trail Making Part B), working memory (forward, reverse, ascending Digit Span), and verbal fluency (Animal Naming and COWA) were calculated based on the non-depressed older adults.

The baseline sample included 210 non-depressed older adults and 465 older adults with major depression (LLD). 150 non-depressed older adults and 235 LLD patients provided three-year follow-up data. Separate ANOVAs revealed a statistically significant interaction between education and depression status at baseline on the composite score of executive functioning F (1, 668) = 8.74, p <.003. Consistent with our hypothesis, LLD with low education performed significantly worse compared to non-depressed with low education (z-score difference -1.35) and this effect was significantly greater than the difference between LLD patients and non-depressed with high education (z-score difference -0.36). No other interactions were found at baseline. Longitudinal analyses also revealed significant interactions between education and depression on memory over time, although sensitivity analyses did not suggest findings consistent with our hypothesis.

Cognitive reserve contribute to group differences between LLD and non-depressed older adults in cognitive performance but may not alter cognitive trajectories over time. Future studies should further explore structural and functional brain changes associated with CR in LLD.

Daily driving behavior is ultimate measure of cognitive functioning requiring multiple cognitive domains working synergistically to complete this complex instrumental activity of daily living. As the world’s population continues to grow and age older, motor vehicle crashes become more frequent. Cognitive and brain reserve are developing constructs that are frequently assessed in aging research. Cognitive reserve preserves functioning in the face of greater loss of brain structure as experienced during cognitive impairment or dementia. This study determined whether cognitive reserve and brain reserve predict changes in adverse driving behaviors in cognitively normal older adults.

Cognitively normal participants (Clinical Dementia Rating 0) were enrolled from longitudinal studies at the Knight Alzheimer’s Disease Research Center at Washington University. Participants (n=186) were ≥ 65 years of age, required to have Magnetic Resonance Imaging (MRI) data, neuropsychological testing data, as well as one full year of naturalistic driving data prior to the beginning of COVID-19 lockdown in the United States (March 2020). Naturalistic driving behavior data was collected via the Driving Real World In-vehicle Evaluation System (DRIVES). DRIVES variables included idle time, over speeding, aggression, number of trips, including those at day and night. MRI was performed on 3T Tesla using a research imaging protocol based upon ADNI that includes a high-resolution T1 MPRAGE for assessment of brain structures to produce normalized whole brain volume (WBV) and hippocampal volume (HV). WBV and HV were each assessed using tertiles comparing the top 66% with the bottom 33% where the bottom represented increased atrophy. The Word Reading subtest of the Wide Range Achievement Test 4 (WRAT 4) was utilized as a proxy for cognitive reserve. WRAT 4 scores were compared with the top 66% and the bottom 33% where the bottom were poor performers. Linear-mixed-effect models adjusted for age, education, and sex.

Participants on average were older (73.7±4.9), college educated (16.6±2.2), and similar sex distribution (males=100, females=86). Analyses showed statistically significant differences in slopes where participants with increased hippocampal and whole brain atrophy were less likely to overspeed (p=0.0035; p=0.0003), drive aggressively (p=0.0016; p<0.0001), and drive during the daytime (p<0.0001; p<0.0001). However, they were more likely to spend more time idling (p=0.0005; p<0.0001) and drive during the nighttime (p=0.003; p=0.0002). Similar findings occurred with the WRAT 4 where participants with lower scores were less likely to overspeed (p=0.0035), drive aggressively (p=0.0024), hard brake (p=0.0180), and drive during the daytime (p<0.0001) while they were more likely to also spend more time idling (p=0.0012) and drive during the nighttime (p=0.0004).

Numerous changes in driving behaviors over time were predicted by increased hippocampal and whole brain atrophy as well as lower cognitive reserve scores proxied by the WRAT 4. These changes show that those with lower brain and cognitive reserve are more likely to restrict their driving behavior and adapt their daily behaviors as they age. These results suggest older adults with lower brain and cognitive reserve are more likely to avoid highways where speeding and aggressive maneuvers are more frequent.

Parkinson’s disease (PD) is one of the most prevalent neurodegenerative conditions that leads to progressive degeneration in areas of the brain that control movement. As the disease progresses, cognition is also frequently affected, primarily executive functioning. Multiple factors may be involved in the relationship between PD and cognitive dysfunction. This study seeks to determine the association between disease duration (i.e., years since PD diagnosis), vascular comorbidities, and cognitive reserve (CR) and their relationship with executive functioning, in a clinic-referred PD population.

Participants included English-speaking subjects with a diagnosis of PD made by the patient’s treating neurologist (i.e., movement disorders specialist) who received their neurological care and had undergone a comprehensive neuropsychological evaluation at Thomas Jefferson University Hospital in Philadelphia, PA over the past five years. The sample consists of 67 patients. Comprehensive medical and psychiatric histories were obtained, and individuals with severe psychopathology (e.g., bipolar disorder or schizophrenia), medical or other neurological disorders (e.g., seizure disorder, stroke, documented head injury that was more severe than a mild TBI or intracranial bleeding) that could account entirely for cognitive impairment were excluded. An overall domain score of executive functioning was calculated by averaging each participant’s T-scores for the individual neuropsychological tests. Regression analysis was utilized to explore the relationship between number of vascular comorbidities, disease duration, and CR, as measured by a composite of formal education and literacy level, with executive functioning performance on neuropsychological testing for this sample.

The model explains 12.1% of the variance of executive functioning performance (F (3, 66) = 2.883, p = 0.043). A significant positive relationship was found between CR and executive functioning (b = .335, p = 0.008). No significant relationships were found between vascular comorbidities or disease duration with executive functioning. The relationship between CR and each neuropsychological measure was explored independently using Pearson correlation (2-tailed). Significant positive correlations were found between CR and WAIS-IV or WASI-II Similarities (r = .49, p < .001), CR and WAIS-IV or WASI-II Matrix Reasoning (r = .46, p = .001), and CR and FAS (r = .26, p = .037). No significant relationships were found between CR and TMT-B (r = .07, p = .565) or CR and Stroop Color and Word Interference (r = .17, p = .240).

Results suggest that CR may be a better predictor of executive functioning in patients with PD than number of vascular comorbidities or disease duration. Stronger premorbid cognitive functioning and better cognitive efficiency may be neuroprotective and stave off cognitive decline in Parkinson’s disease.

Females outperform males on verbal memory tests across the lifespan. Females also exhibit greater Alzheimer’s disease (AD) pathology at preclinical stages and faster atrophy and memory decline during disease progression. Synaptic factors influence the accumulation of AD proteins and may underpin cognitive resilience against AD, though their role in sex-related cognitive and brain aging is unknown. We tested interactive effects of sex and genetic variation in SNAP-25, which encodes a presynaptic protein that is dysregulated in AD, on cognition and AD-related biomarkers in cognitively unimpaired older adults.

Participants included a discovery cohort of 311 cognitively unimpaired older adults (age mean [range]=70 [44-100]; 56% female; education mean=17.3 years; 24% APOE-e4+), and an independent, demographically-comparable replication cohort of 82 cognitively unimpaired older adults. All participants completed neurological examination, informant interview (CDR=0), neuropsychological testing, and blood draw. Participants were genotyped for the SNAP-25 rs105132 (T→C) single-nucleotide polymorphism via Sequenom (discovery cohort) or Omni 2.5M (replication cohort). In vitro models show the C-allele is associated with increased SNAP-25 expression compared to T/T genotype. A subset of the discovery cohort completed structural MRI (n=237) and florbetapir Aβ-PET (n=97). Regression analyses across cohorts examined the interaction of sex and SNAP-25 genotype (T/T homozygotes [53% prevalence] vs. C-carriers [47% prevalence]) on cognitive z-scores (verbal memory, visual memory, executive function, language), adjusting for age, education, APOE-e4, and APOE-e4 x sex. Discovery cohort models also examined sex-dependent effects of SNAP-25 on temporal lobe volumes and Aβ-PET positivity.

SNAP-25 T/T vs. C-carriers did not differ on demographics or APOE-e4 status across cohorts or within sexes. Sex interacted with SNAP-25 to predict verbal memory (p=.024) and language (p=.008) in the discovery cohort, with similar verbal memory differences observed in the replication cohort. In sex-stratified analyses, C-carriers exhibited better verbal memory than T/T carriers among females (d range: 0.41 to 0.64, p range: .008 to .046), but not males (d range: 0.03 to 0.12, p range: .499 to .924). In SNAP-25-stratified analyses, female verbal memory advantages were larger among C-carriers (d range: 0.74 to 0.89, p range: <.001 to .034) than T/T (d range: 0.13 to 0.36, p range: .022 to .682). Sex also interacted with SNAP-25 to predict Aβ-PET positivity (p=.046) such that female C-carriers exhibited the lowest prevalence of Aβ-PET positivity (13%) compared to other groups (23% to 35%). C-carriers exhibited larger temporal lobe volumes across sex, yet this effect only reached statistical significance among females (females: d=0.41, p=.018; males: d=0.26, p=.179). In post-hoc analyses, larger temporal lobe volumes were selectively associated with better verbal memory in female C-carriers (β=0.36, p=.026; other groups: |βs|<0.10, ps>.538).

Among clinically normal older adults, we demonstrate female-specific advantages of carrying the SNAP-25 rs105132 C-allele across cognitive, neural, and molecular markers of AD. The rs105132 C-allele putatively reflects higher endogenous levels of SNAP-25. Our findings suggest a female-specific pathway of cognitive and neural resistance, whereby higher genetically-driven expression of SNAP-25 may reduce likelihood of amyloid plaque formation and support verbal memory, possibly through fortification of temporal lobe structure.

Cognitive reserve (CR) refers to how flexibly and efficiently the individual makes use of available brain resources. Early-life education, midlife social and occupational activities, and later-life cognitive and social interactions are associated with greater CR. Years of education, premorbid intellectual (IQ) functioning, linguistic ability, and occupational complexity are often used as proxies of CR. CR theory seeks to explain discrepancies between the extent of disease pathology and clinical presentation amongst individuals with dementia. In the presence of Alzheimer’s Disease (AD) pathology, higher CR is associated with slower declines in executive functioning (EF). The current study examined the correlation between CR and EF performance across various stages of dementia severity as measured by the total score on the Clinical Dementia Rating Scale (CDRS).

The study cohort consisted of 269 individuals who had completed measures of EF and the CDRS from phase 1 of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Individuals who scored less than 2 on the CDRS were included in the MCI group (n=197), while individuals that scored 2 or higher on the CDRS were included in the dementia group (n=73). A simple linear regression was utilized to compare the MCI group to dementia group across CR and EF performance.

There was significant correlation between CR and EF performance in the MCI group as quantified on total CDRS score (F (200) = .353, p = .0, p < .05). CR was not observed to be predictive of EF in the dementia group (F (200) = .031, p = .666, p > .05).

Findings are consistent with prior research suggesting CR is protective during early stages of dementia, but not in the later disease stages. As prior research has shown the expression of dementia is based on a complex interaction between genetic and lifestyle factors that are unique to each person, future research exploring the potentially protective role of CR amongst pre-symptomatic adults with a genetic predisposition for developing dementia may expand our understanding of the potential role of CR on dementia prevention and progression.