Using a pathologically defined cohort of 4R-tauopathy, we found similar ratios of females and males across the different 4R-tauopathy subtypes without prominent sex differences for co-pathologies, except for Lewy body pathology. Other than vascular pathology, co-pathologies were not frequent across the groups. Females tend to outlive males despite worse overall health and higher rates of disability [28], and this sex difference in survival was preserved in our cohort. To account for this survival bias and potential inclusion bias of females with milder diseases over males with more advanced and severe diseases, we included age as a covariate in our models and also performed sensitivity analyses with age as a moderating variable. These sensitivity analyses revealed the relatively older onset age and less severe symptoms for females compared to males were not necessarily age dependent. Females being less likely to be married/partnered and more likely to be widowed in our cohort couples this survival bias. Most caregivers for people with neurodegenerative disorders including AD, FTD, and LBD, are women [29–31]. Similarly, most co-participants in our cohort were females despite a similar sex distribution across the pathology groups.

Both females and males had a limited clinical diagnostic accuracy during life emphasizing the shortcomings of clinical criteria and the need for biomarkers during life. The participants with pathology data represent older data in the NACC, and the diagnostic criteria for both PSP [32] and CBD [33] have been updated over time providing a better diagnostic accuracy. However, our findings, in line with the literature [9], show that these pathologies are associated with a range of clinical profiles linked to pathologies such as AD, LBD, and other tauopathies. In recognition of these clinical profiles, caregiver report plays an important role for a range of symptoms. Caregiver gender can impact the report of symptoms as well as severity. For instance, women caregivers are more likely to notice subtle change in cognition, behavior, and daily functioning in the early stages of dementia [34]. The higher percentage of females as co-participants in our cohort likely affected our findings. These emphasize the need to incorporate biomarkers for better clinical diagnostic accuracy. With focus on the more affordable and less invasive biomarkers, 4R tau seed amplification assays in skin have been providing promising results for the clinical diagnosis of PSP [35, 36]. As co-pathologies can occur in 4R-tauopathies, use of different biomarkers in combination can provide a better insight into the multiple neurodegenerative pathologies that may be impacting the individual.

Mahale and colleagues reported younger age at onset and more frequent apathy, executive dysfunction, and hyperreflexia, as well as faster progression to severe dysarthria, dysphagia, and cognitive impairment for females with PSP [11]. Despite more frequent PSP-parkinsonism subtype and faster progression to wheelchair dependency for males, females were more likely to experience falls within the first year [11]. Our findings also revealed falls as the most common first motor symptom for females, compared to gait disorder as a more common first motor symptom for males. Since both patient and caregiver sex and gender impact reporting of symptoms [34], changes in gait for females may remain underrecognized prior to falls. In clinically defined PSP cohorts, a study noted faster disease progression for females [10], and another study showed younger age at diagnosis for females with longer survival after diagnosis [37]. In contrast, another study reported no sex differences in disease onset age, symptoms, or progression [13]. Similarly, we did not find a difference in clinical diagnoses, onset age and age at death by sex. Despite studies suggesting worse cognition for females [11, 12] or lack of sex differences for cognition [14], we found less severe dementia and lower likelihood of attention, executive, and memory impairment for females than males. As only 41% of people with PSP pathology had clinical PSP diagnosis in our cohort, it is not surprising that our findings do not completely align with previous findings. However, studies showing lower PSP risk for females with history of estrogen replacement therapy [38], and female-specific benefit with davunetide that enhances tau-microtubule interaction to protect against tauopathy and neurodegeneration [10], support the consideration of sex in PSP for risk, diagnosis, and treatment.

We found a similar prevalence and co-pathology profile for females and males in the CBD group. Clinical diagnosis of FTD was more common than AD and LBD in the CBD group in line with previous literature [33]. Although CBS is typically the most common clinical profile for CBD, unspecified FTD clinical profile was more frequent than CBS. This can be due to participants with neuropathological assessments in the NACC having been clinically assessed prior to the 2013 Armstrong diagnostic criteria for CBD outlining the probable and possible CBS clinical profiles [33]. It also supports the utility of the 4R-tauopathy diagnostic criteria for better sensitivity [6]. Tremors are less common than other movement symptoms in CBD [33]. Accordingly, we noted tremors as the least common movement symptom for both females and males, with females showing even lower incidence than males. Apathy is common in CBD, and other neurodegenerative diseases including PSP, AD, FTD, and LBD [32, 39–41]. There is a male predominance for apathy in AD, FTD, and dementia with Lewy bodies [40], which we also noted in our CBD cohort with older age at behavioral symptom onset for females. In an FTD cohort, females were less likely to have apathy than males despite similar levels of frontotemporal atrophy [42]. Thus, the sex difference for apathy in our cohort can stem from gender-related differences in co-participant report of symptoms and a potential resilience in females with CBD. While we did not find a sex difference for survival in CBD, Aiba and colleagues reported longer survival for females than males without sex differences for clinical profile [43]. Our findings likely differ due to their CBD cohort consisting of people with primarily CBS and PSP clinical diagnoses with movement symptoms, whereas our NACC cohort includes ADRCs collecting data to advance AD and related dementia research.

Behavioral symptoms are common in AGD with depression being one of the most common [19, 44]. Compared to males, females were more likely to have depression but had overall less severe behavioral symptoms with an older age at onset. Interestingly, females were less likely to have clinical LBD diagnosis than males, including lower likelihood of cognitive fluctuations and gait disorder, coupled with a lower Lewy body pathology staging. Previous findings support a lower prevalence and less severe Lewy body pathology in females compared to males [45, 46]. Additionally, females have a lower likelihood of LBD clinical profile than males despite similar or more Lewy body pathology burden [23, 47]. Our findings outline that Lewy body pathology frequency, and clinical associations differ by sex in the overall 4R-tauopathy group and the AGD subtype, suggesting a potential resilience against Lewy body pathology in females. Tau and alpha-synuclein pathologies can enhance the aggregation of one another and have synergistic neurodegenerative effects [48]. In AD, alpha-synuclein co-pathology is associated with faster tau accumulation for females than males [49]. Thus, the interaction of alpha-synuclein and tau for clinical outcomes may differ by sex and depend on the predominant or initial pathology, as well as the type of tauopathy.

In the overall cohort, CTE prevalence differed by sex. Traumatic brain injury (TBI) is associated with CTE and Lewy body pathology [50]. Traditionally, males have higher TBI prevalence [51], however, recent studies have suggested TBI incidence can be higher for females in the age group of > 65 [52]. Outcomes of TBI can differ by sex; females experience more and worse symptoms and more structural changes on magnetic resonance imaging in brain regions that are associated with tau pathology in CTE [53]. Thus, sex differences can occur in the prevalence of pathologies with changes in gender roles in daily life. Sex differences in clinicopathological associations should not be disregarded for tau and Lewy body pathologies.

Other 4R subtype in our cohort included different 4R-tauopathies and had a small number of participants. Thus, the findings from this subtype are more exploratory and should be interpreted cautiously. Older age at cognitive decline onset for females in the Other 4R subtype is consistent with a previous review reporting females 6 years older at symptom onset than males with GGT [15]. Buciuc and colleagues noted eye movement abnormalities, parkinsonism, and behavioral changes as the most common symptoms for GGT [54]. While motor symptoms were observed for half of the males in the Other 4R subtype, females were significantly less likely to experience motor symptoms. However, we were unable to ascertain whether majority of this subtype consisted of people with GGT or another type of 4R-tauopathy.