Cognitive Problems in Perimenopause: A Review of Recent Evidence

Abstract

Purpose of Review

To review recent research regarding cognitive problems during perimenopause, including which menopause-related symptoms, demographic variables, stress exposures, and neural biomarkers are associated with cognitive problems and which interventions demonstrate efficacy at improving cognitive performance.

Recent Findings

Cognitive problems are common during perimenopause and have a significant impact on a substantial proportion of women. Evidence continues to indicate that verbal learning and verbal memory are the cognitive functions that are most negatively affected during perimenopause, and new research suggests that perimenopause may also be associated with deficits in processing speed, attention, and working memory. Recent research suggests that the cognitive profiles of women transitioning through perimenopause are heterogenous – with some showing strengths and others demonstrating weaknesses in particular cognitive domains. Depression, sleep problems, and vasomotor symptoms in perimenopause may be associated with cognitive difficulties. Recent neuroimaging studies are identifying changes in activity patterns within brain regions that correlate with cognitive performance in perimenopause, but future causal studies are needed to understand the neural mechanisms of cognitive problems during this time. Although clinical treatment studies for cognitive concerns have historically focused on postmenopause, some small trials in perimenopausal samples have been conducted recently but are frequently underpowered. Current guidelines from the North American Menopause Society do not support the use of hormone therapy at any age for cognitive problems. Animal research demonstrates that estradiol and levonorgestrel combined may alleviate working memory problems.

Summary

Much progress has been made in understanding how perimenopause impacts cognition, and more research is needed to better identify who is at highest risk and how to meaningfully prevent and alleviate cognitive problems during this reproductive stage. Larger-scale randomized intervention trials specifically during perimenopause are urgently needed to address cognitive concerns in this population of women. More consistent reproductive staging, inclusion of covariates, and analyses examining perimenopause specifically would improve study quality and the ability to draw clear conclusions from this research.

Introduction

Perimenopausal hormonal flux affects multiple body systems, including brain functions. Cognitive difficulties during perimenopause have been reported through subjective self-reports (e.g., [1]) and objective performance-based measures (e.g., [2, 3]). Estrogen, whose receptors are abundant in brain regions critical for cognition, such as the hippocampus and prefrontal cortex, has been implicated in these cognitive changes [4–6]. Cognitive changes over the menopause transition impair daily functioning and warrant clinical attention [1, 7]. While progress has been made in understanding cognitive problems in perimenopause, much remains to be discovered. In this review, we summarize the current state of knowledge and highlight recent research on cognitive problems in perimenopause. Our review focuses on natural menopause and excludes surgical menopause because it lacks a perimenopausal transition period. We cover three main topics: 1) the impact of perimenopause on cognition, 2) factors associated with cognitive function during perimenopause, and 3) interventions for cognitive difficulties in perimenopause.

How is Perimenopause Defined?

The Stages of Reproductive Aging Workshop (STRAW) + 10 staging system defines perimenopause as including three stages: the Early Menopausal Transition (Stage −2), Late Menopausal Transition (Stage −1), and Early Postmenopause (Stage + 1a) [8]; see Fig. 1). Perimenopause is characterized by changes in consecutive menstrual cycle length by seven or more days (Stage −2), followed by 60 or more days of amenorrhea (Stage −1), and concluding after 12 months of amenorrhea (Stage + 1a). Postmenopause starts the day after the final menstrual period but can only be identified retrospectively after 12 consecutive months of amenorrhea. Estrogen levels fluctuate drastically during perimenopause [9, 10], which typically lasts around four years [11]. Vasomotor symptoms like hot flashes and night sweats are common during perimenopause due to changes in reproductive hormones. These hormonal changes are most pronounced in the two years preceding and following the final menstrual period, overlapping with perimenopause [12]. However, studies do not universally use the STRAW + 10 staging system, leading to variability in defining perimenopause and posing challenges in summarizing literature on cognitive problems during this reproductive stage. This review highlights variations in defining perimenopause across studies; we specify the instances in which STRAW + 10 criteria were not used.

Fig. 1.

The Stages of Reproductive Aging + 10 staging system for reproductive aging in women

Impact of Perimenopause on Cognition

Although cognitive problems are common during perimenopause [13], robust prevalence estimates are rare because the majority of studies either assess cognitive problems within an age range considered to be at-risk based on when the perimenopause typically occurs but do not conduct reproductive staging [14] or they do conduct reproductive staging but do not stratify prevalence rates by perimenopause [15–17]. Nevertheless, three recent cross-sectional studies have reported rates of memory and concentration problems based on reproductive stage (pre-, peri-, and postmenopause) ([18–20]; see Table 1). Though differences in scales and questionnaires used make it difficult to compare prevalence rates across populations, the overall message of recent studies is clear: most women report experiencing problems with memory and concentration during the perimenopausal period. This conclusion is supported by an early seminal study that reported memory problems in approximately half of perimenopausal women, such as difficulties with remembering where they put things, what people told them, and whether they had already told someone something [21].

Table 1.

Prevalence rates of self-reported cognitive problems in perimenopause and other reproductive stages

Authors (Year)	Region	Sample Characteristics	Cognitive Measure	Prevalence
Zhang et al. [46]	China	4,063 Chinese women in peri- (52%) and postmenopause (48%)	Validated questionnaire measuring 41 menopause-related symptoms	Hypomnesia: • 65.5% perimenopause • 70.7% postmenopause Difficulty concentrating: • 53.0% perimenopause • 55.3% postmenopause
Lee and Lee [19]	Taiwan	20,882 Taiwanese women ages 40–89 in pre- (27%), peri- (25%), and postmenopause (48%)	Menopause/midlife symptom scale consisting of 19 questions rating severity	Memory loss: • 63.3% premenopause • 66.4% perimenopause • 69.2% postmenopause
Su et al. [20]	China and Japan	365 Chinese and 362 Japanese women ages 40–59 in pre- (Chinese: 54%; Japanese: 49%), peri- (Chinese: 13%; Japanese: 16%), and postmenopause (Chinese: 33%; Japanese: 35%)	Multidimensional inventory for measuring menopause-related symptoms with 60 items	Memory loss: • Chinese o 73.1% premenopause o 76.8% perimenopause o 80.3% postmenopause • Japanese o 92.3% premenopause o 95.0% perimenopause o 90.7% postmenopause Poor concentration: • Chinese o 43.6% premenopause o 74.9% perimenopause o 77.4% postmenopause • Japanese o 88.8% premenopause o 90.0% perimenopause o 86.9% postmenopause

Recent cross-sectional and longitudinal work has further examined how perimenopause affects cognition, either across multiple timepoints within perimenopause or in comparison to pre- and postmenopausal stages. Comparisons of peri- to well-defined postmenopause stages are especially needed; while evidence indicates that cognition declines in peri- relative to premenopause, it is unclear whether and for how long these declines may persist into postmenopause. Cross-sectional studies, however, may be vulnerable to misclassification of reproductive stage due to assessment of menstrual bleeding patterns that rely on recall rather than prospective calendar tracking [22]. Cross-sectional studies may have less sensitivity to detect potential influences of menopause transition stage than longitudinal studies due to the greater influence of confounders in cross-sectional studies. Longitudinal tracking allows participants to serve as their own controls over time, limiting the influence of confounders, and when longitudinal studies enroll all participants during premenopause, the influence of menopause transition stages can be more clearly ascertained. Across both study designs, variability in reproductive staging methods, adjustment for confounders, inclusion of covariates, and cognitive performance measures may account for discrepant findings. Given these important differences between study designs, we review recent evidence from cross-sectional and longitudinal work separately.

Impact of Perimenopause on Cognition: Cross-sectional Studies

Cross-sectional studies that formally test the impact of reproductive stage on cognitive outcomes have historically yielded mixed results, including about how perimenopause cognition compares to postmenopause cognition [23, 24]; recent cross-sectional studies from around the world have had similarly mixed findings, with some finding support for a difference in cognition between peri- and postmenopause in particular and others not [18, 25–29]. A study of over 4,000 women presenting to a menopause clinic in China found that a variety of menopause symptoms, including the “cognitive symptoms” domain comprised of two items (hypomnesia and lack of concentration), were rated as significantly less severe in the perimenopause group¹ compared to the postmenopause² group [18]. In a sample of 315 women from rural Northern India, compared to the postmenopause³ group, poor memory was endorsed more commonly in the menopause transition⁴ group [25]. Among 404 women from rural Northern India categorized into premenopausal,⁵ perimenopausal,⁶ and early⁷ or late⁸ postmenopausal groups, reproductive stage significantly predicted performance on most domains measured by the Mini-Mental State Examination (MMSE) (orientation to time and place; attention and calculation; recall; and language and visuospatial ability), declining across successive reproductive stages [26]. An online study of primarily American and Canadian women (N = 1,529) found that difficulty concentrating and forgetfulness were rated as among the most burdensome symptoms in both the late reproductive stage⁹ and menopause transition¹⁰ groups, but the menopause transition group endorsed more frequent brain fog symptoms like forgetfulness, difficulty concentrating, and difficulty making decisions [27]. However, these studies did not adjust for covariates known to affect cognitive performance, such as age [18, 25–27].

In contrast, two studies that adjusted for covariates did not find a significant difference between the perimenopause/menopause transition and other reproductive stages on cognitive performance [28, 29]. In a sample of 702 urban women living in Sub-Saharan Africa who participated in the Study of Women Entering and in Endocrine Transition (SWEET), cognitive performance on processing speed and incidental recall tasks did not differ by reproductive stage (late reproductive, early menopausal transition, late menopausal transition, early postmenopause, and late postmenopause using STRAW + 10 criteria) after adjusting for age, BMI, sociodemographic variables, and menopause and mental health symptoms [28]. Similarly, analyses from a cross-sectional sample of healthy Argentinian women (N = 100) did not find evidence for an impact of reproductive stage (pre-,¹¹ peri-,¹² postmenopause,¹³ based on an earlier version of STRAW criteria [30]) on tests of executive functioning (working memory, verbal fluency, inhibitory control, planning, cognitive flexibility) when controlling for age [29].

Impact of Perimenopause on Cognition: Longitudinal Studies

Seminal longitudinal studies demonstrated that verbal memory and verbal learning decline from pre- to perimenopause, independent of age and other potential confounders [2, 3]. Cohorts from the Penn Ovarian Aging Study (POAS [2]¹⁴) and the Study of Women’s Health Across the Nation (SWAN [3]¹⁵) showed verbal decrements in perimenopause compared to premenopause, or compared to pre- and postmenopause, respectively. The Rochester Investigation of Cognition Across Menopause (RICAM) cohort, which used STRAW + 10 criteria, demonstrated declines in the final year of perimenopause—in the first year postmenopause (Stage + 1a), or the first 12 months after the final menstrual period—relative to the late premenopause and late menopausal transition stages [24]. Until more recently, evidence had been mixed regarding the impact of perimenopause on processing speed [3, null findings in 2, 31], was less robust for verbal fluency as only one study had examined the latter [31], and did not indicate an effect on attention and working memory [24, null findings in 2, 3, 31]. Recent analyses from longitudinal cohorts have added meaningfully to this knowledge base [32–34].

The Women’s Interagency HIV Study (WIHS) assessed cognitive performance changes on a biennial neuropsychological test battery over the menopause transition¹⁶ in a sample of primarily low-income women of color (N = 443; M = 3.8 assessments/woman over the study), a subset of which had HIV (n = 291) [35]. Verbal learning, verbal memory, and attention and working memory declined from pre- to early perimenopause and from pre- to postmenopause in the overall sample. Similar findings were observed in women with HIV; potential interactions between HIV status and reproductive stage on cognitive performance were not tested. The declines in attention and working memory in early perimenopause in a longitudinal study represent novel findings. Although it is possible that sociodemographic factors may explain why declines in attention and working memory were observed in this sample but not other longitudinal samples [2, 3, 31], a cross-sectional study using the same cognitive task with a primarily White (91%) sample found decrements in early postmenopausal women compared to premenopausal women [24]. Null findings in previous longitudinal studies may be explained by the fact that less difficult attention and working memory tasks were used, which could have resulted in a ceiling effect.

The Estrogenic Regulation of Muscle Apoptosis study staged women (N = 342; 2 assessments/woman) into early perimenopause¹⁷ or late perimenopause¹⁸ using follicle stimulating hormone (FSH) levels and menstrual cycle pattern, tested their cognitive performance, and then tested them again once they reached postmenopause¹⁹ [33]. Of the cognitive functions tested, psychomotor speed, working memory, set-shifting, and visual memory performance improved in postmenopause compared to early or late perimenopause whereas verbal fluency remained the same. These findings suggest that cognitive performance is comparable or worse during perimenopause relative to postmenopause.

Among a midlife sample (N = 2,411) from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort, including women in pre-, peri-, and postmenopause (max = 3 assessments/woman), older reproductive age (measured in years relative to FMP), higher FSH levels, and higher luteinizing hormone (LH) levels were associated with worse performance on tests of verbal learning and verbal memory, independent of age [34]. No consistent relationships were found between reproductive age and hormones with performance on working memory, processing speed, verbal intelligence, and verbal fluency tests. Although this study did not focus solely on perimenopause, these findings provide support that verbal learning and verbal memory are negatively impacted around the time of menopause and are associated with higher levels of reproductive hormones FSH and LH, both of which increase around menopause.

The RICAM longitudinal study used latent profile analysis to identify subsets of women based on cognitive functioning during STRAW + 10 defined perimenopause (N = 85; M = 3.6 assessments/woman; [32]. This profile analysis approach contrasts with looking at average changes in cognition as has been done in many previous longitudinal analyses. Four profiles were identified: Profile 1 was cognitively normal, Profile 2 had deficits in verbal learning and verbal memory, Profile 3 had strengths in verbal learning and verbal memory, and Profile 4 had strengths in executive function and attention. These results suggest substantial heterogeneity in women’s cognitive function during perimenopause.

In sum, recent longitudinal research strengthens evidence that perimenopause negatively impacts verbal learning and verbal memory [35]. Additionally, this research provides novel evidence that the time around menopause may also negatively impact processing speed [34] and attention and working memory [33, 35]. Profile analysis highlights the between-person heterogeneity of perimenopause cognitive performance [32]. One study brought focus to a new population: participants of color with low incomes, HIV, and potentially higher risk for cognitive problems [35]. Future research should systematically evaluate individual differences that may shape trajectories of cognitive difficulties across perimenopause.

Factors Associated with Cognitive Function during Perimenopause

Menopause-Related Symptoms

Previous studies have correlated cognitive problems with other menopause-related symptoms, hypothesizing that the latter may directly or indirectly underlie the cognitive difficulties reported during perimenopause (reviewed in [36]). Recent research on perimenopausal and midlife women has continued to show a relationship between cognitive difficulties and anxiety [37, 38], depressed mood [32, 38], fatigue [37], sleep problems [39], vasomotor symptoms [14, 32, 38], and reproductive hormones [32, 34, 39]. However, only two of these studies examined the relationship specifically in perimenopausal women [32, 39], whereas the other studies grouped perimenopausal women with women in other reproductive stages and controlled for reproductive stage rather than testing whether the relationship was stronger in perimenopausal women [14, 37, 38]. We only focus on studies that assessed the relationship between cognitive decline and menopause-related symptoms in perimenopause specifically, and future research is needed to determine whether anxiety and fatigue influence the nature of cognitive problems in the perimenopause (moderation) or whether they underlie the relationship between reproductive stage and cognitive problems (mediation).

In the recent profile analysis conducted from the RICAM longitudinal study in perimenopausal women, after adjusting for stage within perimenopause, age, and race, the verbal learning and memory strengths profile was associated with fewer depressive symptoms compared to the cognitively normal profile, and the verbal learning and verbal memory weaknesses profile was associated with a trend for more depressive symptoms than the cognitively normal profile [32]. In adjusted models, compared to the cognitively normal profile, the verbal learning and verbal memory weaknesses profile was associated with more sleep disturbance and the verbal learning and memory strengths profile was associated with fewer vasomotor symptoms [32].

In peri- but not postmenopausal Polish women, severity of insomnia was associated with simple attention [39], suggesting that sleep problems may impact simple attention specifically (or more strongly) in perimenopause. Insomnia severity was not related to complex memory, verbal memory, visual memory, psychomotor speed, reaction time, complex attention, cognitive flexibility, processing speed, executive function, or motor speed in either peri- or postmenopausal women.

Reproductive Hormones

Contrary to expectations, cognitive deficits were linked to less variability in FSH and 17b-estradiol as well as lower FSH within a perimenopausal sample [32]. In another study, higher serum estradiol concentration correlated with faster processing speed in post- but not perimenopausal women [39].

Taken together, recent findings suggest that depression, sleep problems, vasomotor symptoms, and reproductive hormones may be associated with cognition specifically during perimenopause.

Demographic Factors

Women with lower incomes, a sample observed in the WIHS, may be more vulnerable to prolonged effects of hormonal flux because of potential exposure to multiple risk factors relevant to cognitive dysfunction, including lower education and higher trauma exposure [35]. POAS findings indicated an overall impact of race on performance on cognitive tasks but failed to find a differential impact of menopause stage on cognitive performance between African American and White women [2]. RICAM findings suggest that identifying as White and having a higher education tend to be associated with cognitively normal or strong profiles, though this cohort included very few non-White identifying participants [32]. These demographic and associated factors require additional attention, including with respect to intervention.

Adverse Childhood Experiences (ACEs) and Inflammatory Markers

Cross-sectional analyses from the POAS longitudinal cohort revealed interactive effects of childhood adversity exposure, inflammatory marker levels, and reproductive stage on cognitive performance (N = 167; [40]). During the perimenopause,²⁰ higher adverse childhood experiences (ACE) exposure (ACE ≥ 2) was associated with worse immediate verbal recall at higher levels of inflammatory marker tumor necrosis factor-α (TNF-α) while controlling for relevant covariates, including age at study baseline. While cross-sectional analyses prohibit causal conclusions, these findings motivate future research to test whether inflammatory markers impact verbal cognitive performance specifically during perimenopause among women with higher ACE exposures. These results suggest potential utility of screening for previous ACE exposure in midlife women to guide clinicians in recommending lifestyle modifications or targeted interventions to mitigate inflammation in this higher-risk group.

Neural Correlates

Across the brain, glucose metabolism starts declining during perimenopause and continues into postmenopause, likely due in part to estrogen’s role in bioenergetics and the widespread expression of estrogen receptors throughout the brain [41]. It is unknown to what extent this hypometabolism, and other neurological changes, are associated with cognitive deficits in perimenopause. Five recent studies tested whether neurological changes correlate with cognitive task performance in perimenopausal women adjusting for age [42–46], providing initial evidence for which brain regions might underlie perimenopausal cognitive changes.

Three studies found brain regions with volumetric and/or activity changes in perimenopause versus premenopause and/or postmenopause, but none correlated with cognitive performance [42, 44, 45]. Two other studies, however, did find correlations between neuroimaging and cognitive measures [43, 46]. One study suggested that reduced right superior frontal gyrus activity, a region involved in working memory, may be related to cognitive deficits in perimenopause; in perimenopausal compared to premenopausal women, activity in this area was lower and MMSE cognitive impairment was worse [43]. Another study indicated that spontaneous activity in the left inferior temporal gyrus, a region involved in processing visual information, was lower in perimenopausal relative to postmenopausal women and was positively correlated with reaction time on the Stoop color-word test, which measures the ability to inhibit cognitive interference [46]. However, because reaction time was faster in perimenopausal than postmenopausal women, lower activity in the left inferior temporal gyrus may not be related to cognitive deficits. These correlations could be spurious and not mechanistically explanatory; with the exception of [42], these studies were not a priori analyzing brain regions or networks known to be involved in cognition. Future fMRI studies examining brain activity during cognitive task performance in perimenopausal women will help elucidate causal mechanisms of cognitive deficits in this population.

Future studies should also consider the relationship between neural biomarkers, cognitive deficits, and risk for Alzheimer’s disease or dementia during perimenopause. A recent study revealed that perimenopausal women had a higher amyloid-β load brain-wide than premenopausal women, and this difference was heightened in women with the E4 isoform of apolipoprotein E [45]. Unexpectedly, however, this increased amyloid-β load in perimenopausal women was not significantly associated with reduced performance across multiple cognitive domains, including memory and language. A substantial amount of research is still needed to understand cognitive impairments during perimenopause on a neurological level, and the possible connection to Alzheimer’s disease and dementia risk.

Interventions for Cognitive Difficulties in Perimenopause

Despite the potential causal role of estradiol in perimenopausal cognitive complaints [4–6], no large-scale randomized controlled trials have tested whether administration of estrogens, also known as menopause hormone therapy (MHT), improves cognitive problems in perimenopausal women; studies in postmenopausal women have shown no effects overall in cognitive self-report or performance [for a review see 47, 48]. The critical window hypothesis, which suggests that MHT may be more beneficial for cognition if given to women close to the onset of the postmenopause, has yet to be evaluated despite being plausible [for review see 49]. Given the lack of current evidence, the North American Menopause Society does not recommend MHT for the treatment of cognitive complaints at any age during the menopause transition [50]. However, recent clinical studies described below have studied cognitive effects of transdermal estradiol, raloxifene, or a phytoestrogen administered in perimenopause in groups of women with psychiatric disorders [51, 52].

Interventions for Women with Psychiatric Disorders

Two recent studies have investigated the cognitive effects of hormonal interventions during perimenopause in women with specific psychiatric disorders, namely major depressive disorder [51] and schizophrenia [52]. In the first study, 62 perimenopausal women with active major depressive disorder were randomized to one of four interventions for eight weeks: (1) transdermal estradiol, (2) raloxifene (selective estrogen receptor modifier with mixed estrogen agonist/antagonist properties), (3) a phytoestrogen preparation of plant-derived estrogen-like compounds, or (4) placebo [51]. Treatment groups showed no differential improvements on cognition, as assessed by week eight secondary outcome measures of verbal memory, working memory, or visual memory, controlling for baseline performance. Moreover, no intervention demonstrated significant differential benefit over placebo for depression symptoms.

In the second study, 69 women with schizophrenia were randomized to receive either raloxifene or placebo and then evaluated on verbal memory, visual naming and memory, verbal fluency, and working memory [52]. Interestingly, raloxifene improved verbal memory in pre- and postmenopausal women but not perimenopausal women, and improved verbal fluency in perimenopausal women (but not pre- or postmenopausal women). However, raloxifene improved picture naming regardless of menopausal stage.

Together, these findings highlight the differential effects that interventions targeting the estrogen receptor can have on cognition depending on reproductive stage within populations with specific psychiatric disorders. Further research is needed to better understand these differential effects and their underlying mechanisms, as well as whether these findings generalize to populations without psychiatric conditions.

Interventions for Cognition in Animal Models of Perimenopause

Animal studies offer insight on possible hormone therapy treatments for perimenopausal cognitive problems. Though effects of hormone administration on cognition in ovariectomized rodents has been well studied [53, 54], ovariectomy in rodents models surgical menopause. Natural menopause is better modeled with follicle depletion using the ovarian toxin, vinylcyclohexan diepoxide (VCD), with which ovaries remain intact but ovarian follicles and endogenous estradiol decrease [55]. Recent VCD model research indicates that hormone treatment produces varied effects on cognition depending on the regimen, such as estradiol-only, estradiol and synthetic progestin, or progesterone-only. For example, estradiol administration in VCD-treated rodents improved working memory performance compared to control during initial learning, but increased working memory errors once the task was learned [56]. In another study, VCD-treated rats receiving both estradiol and synthetic progestin (levonorgestrel) exhibited better working memory than rats receiving only estradiol [57]. Furthermore, progesterone-only treated rats had decrements in working memory compared to other hormone treatments and control.

Next Steps for Treating Cognitive Difficulties in Perimenopause

More research is urgently needed to identify efficacious treatments for perimenopausal cognitive deficits, including in generalizable samples. Large-scale placebo-controlled studies would be beneficial, specifically testing the effects of (1) non-hormonal agents with action on estrogen receptors, such as raloxifene and phytoestrogens, or (2) more traditional steroid hormone agents used in MHT. Animal research in models of perimenopause suggests a combination of estradiol and levonorgestrel may improve working memory, though this should be tested in humans and on the domains of cognition frequently affected by menopause (i.e., verbal memory).

Current Treatment Recommendations

Despite the lack of evidence for interventions designed to address cognitive complaints specifically in perimenopause, women may benefit from (1) using off-label pharmacotherapies that could improve cognitive functioning, (2) treating psychiatric disorders that could contribute to cognitive difficulties, and (3) engaging in healthy behaviors that promote overall brain function.

MHT remains the recommended treatment for vasomotor symptoms in perimenopause [50], and given associations between vasomotor symptoms and cognition [58–60], treating hot flashes and sweating during perimenopause (that often impair sleep) has the potential to help improve cognition; however, this has not yet been directly tested [61]. In terms of medications, lisdexamfetamine and atomoxetine have shown promise in preliminary studies testing their efficacy when used off-label to improve executive function in postmenopausal women without ADHD, but this still needs to be evaluated in perimenopausal women [62–64].

Comorbid psychiatric disorders are associated with cognitive impairment regardless of reproductive status and, thus, deserve aggressive treatment to limit their contribution to cognitive impairment in perimenopause; evidence indicates positive impact on cognition of depression treatment during perimenopause, but the impact of treating insomnia or anxiety on perimenopausal cognition has not been examined. In individuals with major depressive disorder, antidepressants can improve aspects of cognition, particularly delayed recall [65]. Only a few studies have tested the effect of antidepressants on cognition specifically during the menopause transition. One open-label trial on vortioxetine in perimenopausal and early postmenopausal women with major depressive disorder noted significant improvements in self-reported cognitive function and performance on a psychomotor speed task (N = 27) [66]. Determining which specific agents might be particularly effective for cognition in perimenopausal depression will require additional study. In the meantime, adequately screening for and addressing psychiatric disorders in perimenopause remains warranted to minimize their potential impact on cognition.

General strategies that have been shown to promote brain health and prevent cognitive decline include treating physical health conditions that impact cognitive function (e.g., hypertension) as well as engaging healthy behaviors (e.g., exercising regularly, eating a Mediterranean diet, avoiding smoking and excessive alcohol, maintaining social connections, and keeping cognitively active) [67–72]. While these lifestyle interventions have not been tested for their efficacy in improving cognitive functioning explicitly during perimenopause, we and others recommend them as potentially helpful strategies [47]. At present, lifestyle factors (e.g., diet, exercise) and lifetime hormone exposure (e.g., use of hormonal contraceptives, pregnancies) were rarely controlled for in the examined studies; thus, the effect of these variables on perimenopausal cognition has not been a focus of the studies included in this review. More work is needed to understand their impact during this life stage.

Conclusion

Recent research has further characterized cognitive difficulties that can arise during perimenopause, distinguished distinct profiles of weaknesses or strengths in cognitive domains during perimenopause, and identified potential individual risk factors that may influence how perimenopause affects cognition. This work made critical advances towards more fully appreciating the diversity of women’s cognitive experiences during perimenopause, as well as identifying groups of women who may be at highest risk for cognitive concerns during perimenopause. Initial neuroimaging studies have begun to examine how changes in brain activity patterns associate with cognitive performance during perimenopause, but much research remains to be conducted in this area, particularly with respect to identifying causal neural mechanisms. Sufficiently powered treatment research for perimenopausal women experiencing cognitive problems is critically needed, and to date has been quite limited. While off-label pharmacotherapy and engaging in brain health promoting activities are currently a treatment option, additional, more targeted intervention options are necessary to alleviate the perimenopausal cognitive concerns that affect so many individuals.

Future research can build upon this foundation by using high-quality methods, including consistent use of STRAW + 10 reproductive staging criteria, appropriate inclusion of covariates, such as age and other demographic variables, and conducting analyses examining the perimenopause specifically. Additional attention to identifying whether and when perimenopausal cognitive difficulties resolve in the postmenopause will be beneficial. Better understanding the correlates and trajectories of perimenopausal cognitive difficulties will inform preventative and intervention strategies and will support the work yet to be done on identifying efficacious treatments for perimenopausal women with cognitive concerns.