A Lifecourse Perspective on Female Sex-Specific Risk Factors for Later Life Cognition.

PURPOSE OF REVIEW: The prevalence of Alzheimer's disease and related dementias is greater in women compared to men. We provide a review of female sex-specific risk factors across the lifecourse for cognition in older adulthood, highlighting areas that need further study. RECENT FINDINGS: Pregnancy may affect late-life cognition, with adverse pregnancy outcomes associated with an increased risk of cognitive decline but parity providing a protective effect. Cumulative estrogen exposure, influenced by age of menarche, menopause, and exogenous estrogen use, may modify a woman's risk for dementia. Menopause transition-associated symptoms may impact cognitive health at the time of the symptoms, but long-term effects remain unknown. As compared to natural menopause, surgical menopause seems to increase the risk for cognitive impairment. Studies that have assessed the association between women's reproductive health and cognition have produced conflicting results. Future studies that address these inconsistencies among diverse populations are needed to better care for women throughout their lives.

Cognitive status and demographics modify the association between subjective cognition and amyloid.

OBJECTIVE: This study examined the effect of cognitive status, education, and sex on the association between subjective cognitive decline (SCD) and Alzheimer's disease (AD) biomarkers in non-demented older adults. METHODS: Vanderbilt Memory and Aging Project participants (n = 129), dementia or stroke free, completed fasting lumbar puncture, SCD assessment, and cognitive assessment. Cerebrospinal fluid (CSF) biomarkers for AD were analyzed. Linear regression models related SCD to CSF AD biomarkers and follow-up models assessed interactions of SCD × cognitive status, sex, reading level, and education on AD biomarkers. RESULTS: In main effect models, higher SCD was associated with more amyloidosis (p-values <0.004). SCD was not associated with tau, p-tau, or neurofilament light (NFL) levels (p-values >0.38). SCD score interacted with cognitive status (p < 0.02), sex (p = 0.03), and education (p-values <0.005) on amyloidosis. In stratified models, higher SCD was associated with more amyloid in cognitively unimpaired (p-values <0.003), men (p = 0.0003), and higher education. No SCD score × reading-level interaction was found (p-values >0.51) though SCD related to amyloid markers in the higher reading-level group (p-values <0.004). INTERPRETATION: Higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes prior to objective cognitive impairment, in men, and those with higher quantity and quality of education and highlight the importance of considering these factors.

Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease.

INTRODUCTION: The effects of sex, race, and Apolipoprotein E (APOE) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized. METHODS: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. RESULTS: Sex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION: There are prominent differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.

Sex and Education Modify the Association Between Subjective Cognitive Decline and Amyloid Pathology.

Background: Subjective cognitive decline (SCD) may be an early risk factor for dementia, particularly in highly educated individuals and women. This study examined the effect of education and sex on the association between SCD and Alzheimer's disease (AD) biomarkers in non-demented older adults. Method: Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=156, 72±6 years, 37% mild cognitive impairment, 33% female) completed fasting lumbar puncture, SCD assessment, and Wide Range Achievement Test-III Reading subtest to assess reading level at baseline as a a proxy for educational quality. Cerebrospinal fluid (CSF) biomarkers for AD (ß-amyloid 42 (Aß42), Aß42/40 ratio, phosphorylated tau (p-tau), tau, and neurofilament light (NfL)) were analyzed in batch. Linear mixed effects models related SCD to CSF AD biomarkers and follow-up models assessed SCD x sex, SCD x reading level , and SCD x education interactions on AD biomarkers. Result: In main effect models, higher SCD was associated with lower Aß42 and Aß42/40 ratio (p-values<0.004). SCD was not associated with tau, p-tau, or NfL levels ( p- values>0.38). SCD score interacted with sex on Aß42/40 ratio ( p =0.03) but no other biomarkers ( p -values>0.10). In stratified models, higher SCD was associated with lower Aß42/40 ratio in men ( p =0.0003) but not in women ( p =0.48). SCD score interacted with education on Aß42 ( p =0.005) and Aß42/40 ratio ( p =0.001) such that higher education was associated with a stronger negative association between SCD and amyloid levels. No SCD score x reading level interaction was found (p-values> 0.51) though significant associations between SCD and amyloid markers were seen in the higher reading level group (p-values<0.004) but not the lower reading level group (p-values>0.12) when stratified by a median split in reading level. Conclusion: Among community-dwelling older adults free of clinical dementia, higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes in men and individuals with higher quantity and quality of education. SCD was not associated with CSF markers of tau pathology or neurodegeneration. These findings suggest that considering sex and education is important when assessing SCD in older adults.

Clinical and demographic factors modify the association between plasma phosphorylated tau-181 and cognition.

INTRODUCTION: Plasma phosphorylated tau181 (p-tau181) associations with global cognition and memory are clear, but the link between p-tau181 with other cognitive domains and subjective cognitive decline (SCD) across the clinical spectrum of Alzheimer's disease (AD) and how this association changes based on genetic and demographic factors is poorly understood. METHODS: Participants were drawn from the Alzheimer's Disease Neuroimaging Initiative and included 1185 adults aged >55 years with plasma p-tau181 and neuropsychological test data. Linear regression models related plasma p-tau181 to neuropsychological composite and SCD scores with follow-up models examining plasma p-tau181 interactions with cognitive diagnosis, APOE ε4 carrier status, age, and sex on cognitive outcomes. RESULTS: Higher plasma p-tau181 was associated with worse memory, executive functioning, and language abilities, and greater informant-reported SCD. Visuospatial abilities and self-report SCD were not associated with plasma p-tau181. Associations were generally stronger in MCI or dementia, APOE ε4 carriers, women, and younger participants. DISCUSSION: Higher levels of plasma p-tau181 are associated with worse neuropsychological test performance across multiple cognitive domains; however, these associations vary based on disease stage, genetic risk status, age, and sex.

Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults.

Importance: Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele. Objective: To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition. Design, Setting, and Participants: This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022. Main Outcomes and Measures: Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons. Results: Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (ß = -0.071, SE = 0.014; P = 9.6 × 10-7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (ß = -0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals. Conclusions and Relevance: In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.

The association of vasomotor symptoms during the menopausal transition and cognition in later life.

OBJECTIVE: The majority of women experience vasomotor symptoms (VMS) during the menopausal transition. Whether self-reported VMS are associated with cognitive test performance later in life remains unclear. The goal of this study was to determine whether a greater burden of VMS is associated with poor later-life cognition. METHODS: The Wisconsin Longitudinal Study is a prospective study of randomly selected Wisconsin high school graduates of the class of 1957. At ages 65 and 72, a random subset of participants completed six cognitive tests, including similarities, letter and category fluency, immediate and delayed word recall, and digit ordering. Nested regression models were used to examine the association between extent of VMS, assessed at age 54, and baseline cognition at 65, adjusting for early-life socioeconomic status, women's reproductive health variables, intelligence quotient, and midlife income. This series of models was also used to examine the association between VMS and change in cognition score from age 65 to 72. In sensitivity analyses, models were repeated in a sample using multiple imputation for missing covariates. RESULTS: Of the 5,326 women enrolled, 874 had data onVMS, covariates, and all cognitive tests. In an unadjusted model, higher VMS were associated with a lower similarities score (b = -0.09 95% CI -0.16 to -0.02) at age 65 but no other cognitive tests. In adjusted models, VMS were not related to cognition at age 65 or change in cognition. Results remained similar with multiple imputation. CONCLUSIONS: Our study does not support a relationship between self-reported VMS and cognition later in life.

Motor features associated with cognition in non-demented individuals with essential tremor.

INTRODUCTION: Essential tremor (ET) is a clinically heterogeneous disease characterized by motor and non-motor features, including cognitive impairment. In a cross-sectional analysis, we determined whether the presence and severity of motor features of ET are associated with cognitive performance. METHODS: Participants enrolled in a study that used motor and neuropsychological measures to characterize a cohort of ET subjects. Action tremor severity and additional motor features (rest tremor, intention tremor, cranial tremor, dystonia, tandem gait missteps) were assessed in non-demented participants. Participants completed a cognitive test protocol assessing domains of memory, executive function, attention, visuospatial ability, and language. An average z-score was calculated to represent global cognition. RESULTS: There were 204 ET participants (mean age 78.6, range 55-95). Participants with 10 missteps were more likely to have MCI than those with 0 or 1 misstep (p < 0.001). In unadjusted linear regression models, action tremor severity (p = 0.010), rest tremor (p < 0.001), and tandem gait missteps (p < 0.001) were negatively associated with global cognition. In adjusted models, only tandem gait missteps were negatively associated with global cognition (p < 0.001). Missteps were also negatively associated with memory (p < 0.001), executive function (p < 0.001), attention (p = 0.011), and visuospatial function (p = 0.043). No other motor features were associated with global cognition in adjusted models (p > 0.05). CONCLUSION: Among non-demented participants with ET, there is an association between cognitive performance and tandem gait missteps, but no other motor features of ET. This is a first step in establishing impaired tandem gait as a possible indicator of cognitive impairment in patients with ET.