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.

There are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer’s dementia.

We studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates.

Higher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: β = −0.33, p = .002; Cohort 2: β = −0.36, p = .03) and parietal ROIs (Cohort 1: β = −0.31, p = .01; Cohort 2: β = −0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: β = −0.38, p = .01; Cohort 2: β = −0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP.

Plasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.

The relationship between wisdom and fluid intelligence (Gf) is poorly understood, particularly in older adults. We empirically tested the magnitude of the correlation between wisdom and Gf to help determine the extent of overlap between these two constructs.

Cross-sectional study with preregistered hypotheses and well-powered analytic plan (https://osf.io/h3pjx).

Memory and Aging Center at the University of California San Francisco, located in the USA.

141 healthy older adults (mean age = 76 years; 56% female).

Wisdom was quantified using a well-validated self-report-based scale (San Diego Wisdom Scale or SD-WISE). Gf was assessed via composite measures of processing speed (Gf-PS) and executive functioning (Gf-EF). The relationships of SD-WISE scores to Gf-PS and Gf-EF were tested in bivariate correlational analyses and multiple regression models adjusted for demographics (age, sex, and education). Exploratory analyses evaluated the relationships between SD-WISE and age, episodic memory performance, and dorsolateral and ventromedial prefrontal cortical volumes on magnetic resonance imaging.

Wisdom showed a small, positive association with Gf-EF (r = 0.181 [95% CI 0.016, 0.336], p = .031), which was reduced to nonsignificance upon controlling for demographics, and no association with Gf-PS (r = 0.019 [95% CI −0.179, 0.216], p = .854). Wisdom demonstrated a small, negative correlation with age (r = −0.197 [95% CI −0.351, −0.033], p = .019), but was not significantly related to episodic memory or prefrontal volumes.

Our findings indicate that most of the variance in wisdom (>95%) is unaccounted for by Gf. The independence of wisdom from cognitive functions that reliably show age-associated declines suggests that it may hold unique potential to bolster decision-making, interpersonal functioning, and other everyday activities in older adults.

Clinically normal older adults (52–92 years old) were followed longitudinally for up to 8 years after completing a memory paradigm at baseline [Story Recall Test (SRT)] that assessed delayed recall at 30 min and 1 week. Subsets of the cohort underwent neuroimaging (N = 134, mean age = 75) and neuropsychological testing (N = 178–207, mean ages = 74–76) at annual study visits occurring approximately 15–18 months apart. Mixed-effects regression models evaluated if baseline SRT performance predicted longitudinal changes in gray matter volumes and cognitive composite scores, controlling for demographics.

Worse SRT 1-week recall was associated with more precipitous rates of longitudinal decline in medial temporal lobe volumes (p = .037), episodic memory (p = .003), and executive functioning (p = .011), but not occipital lobe or total gray matter volumes (demonstrating neuroanatomical specificity; p > .58). By contrast, SRT 30-min recall was only associated with longitudinal decline in executive functioning (p = .044).

Memory paradigms that capture longer-term recall may be particularly sensitive to age-related medial temporal lobe changes and neurodegenerative disease trajectories. (JINS, 2020, xx, xx-xx)