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Cited by 339Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsSex and Gender in Healthcare

Sex differences in Alzheimer’s disease and common neuropathologies of aging

Open access
Oveisgharan, Shahram, Arvanitakis, Zoe, Yu, Lei, Farfel, Jose, Schneider, Julie A., Bennett, David A.·2018·Acta Neuropathologica
DOI 10.1007/s00401-018-1920-1PMC PMC6279593
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Abstract

Alzheimer’s dementia is significantly more common in women than in men. However, few pathological studies have addressed sex difference in Alzheimer’s disease (AD) and other brain pathologies. We leveraged postmortem data from 1453 persons who participated in one of two longitudinal community-based studies of older adults, the Religious Orders Study and the Rush Memory and Aging Project. Postmortem examination identified AD pathologies, neocortical Lewy bodies, DNA-binding protein 43 (TDP-43), hippocampal sclerosis, gross and micro infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. Linear and logistic regressions examined the association of sex with each of the pathologic measures. Two-thirds of subjects were women (n = 971; 67%), with a mean age at death of 89.8 (SD = 6.6) years in women and 87.3 (SD = 6.6) in men. Adjusted for age and education, women had higher levels on a global measure of AD pathology (estimate = 0.102, SE = 0.022, p < 0.001), and tau tangle density in particular (estimate = 0.334, SE = 0.074, p < 0.001), and there was a borderline difference between women and men in amyloid-β load (estimate = 0.124, SE = 0.065, p = 0.056). In addition, compared to men, women were more likely to have more severe arteriolosclerosis (OR = 1.28, 95% CI:1.04–1.58, p = 0.018), and less likely to have gross infarcts (OR = 0.78, 95% CI:0.61–0.98, p = 0.037), although the association with gross infarct was attenuated after controlling for vascular risk factors. These data help elucidate the neuropathologic footprint of sex difference in AD and other common brain pathologies of aging.

AI snapshot

Written from the paper’s full text.

TL;DR

In 1,453 autopsies from two community-based aging cohorts, women had more Alzheimer’s disease (AD) pathology, especially tau tangle density, and more severe arteriolosclerosis than men. These differences were not explained by age, APOE ε4, menopause type, or hormone replacement therapy.

Key findings

  • Among 1,453 deceased participants (971 women, 67%; mean age at death 89.8 years in women vs. 87.3 in men), women had higher global AD pathology after adjustment for age and education (estimate=0.102, SE=0.022, p<0.001) and higher tau tangle density (estimate=0.334, SE=0.074, p<0.001); Aβ load was borderline (estimate=0.124, SE=0.065, p=0.056).
  • More than 60% met pathologic criteria for AD, with a higher percentage in women (68%) than men (58%); women were 35% more likely to have a pathologic AD diagnosis (OR=1.35, 95% CI:1.06–1.72).
  • Women were more likely to have severe arteriolosclerosis (OR=1.28, 95% CI:1.04–1.58, p=0.018) and less likely to have gross infarcts (OR=0.78, 95% CI:0.61–0.98, p=0.037), though the gross infarct association attenuated after controlling for vascular risk factors (OR=0.80, 95% CI:0.63–1.02, p=0.072).
  • No sex differences were found for neocortical Lewy bodies, TDP-43, hippocampal sclerosis, microinfarcts, atherosclerosis, or cerebral amyloid angiopathy; no interaction was found between sex and APOE ε4, and both natural- and surgical-menopause women had higher AD pathology than men.

Methods

  • Cross-sectional postmortem analysis of 1,453 participants from the Religious Orders Study and Rush Memory and Aging Project, two longitudinal community-based cohorts of older adults without dementia at entry; follow-up exceeded 90% and autopsy rate exceeded 85%.
  • Neuropathologic evaluation included immunohistochemistry and stereology for tau tangle density and Aβ load across 8 cortical regions, a global AD pathology score from Bielschowsky silver-stained neuritic plaques, diffuse plaques, and neurofibrillary tangles, plus assessments of Lewy bodies, TDP-43, hippocampal sclerosis, infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy.
  • Linear and logistic regressions adjusted for age and education examined sex associations, with additional models for age and APOE ε4 interactions, menopause type/age, hormone replacement therapy, vascular risk factors, and cohort; analyses used SAS version 9.4.

Limitations

  • The paper states participants had higher education levels and more than 95% were Caucasian, reducing generalizability; tau measures described only neuronal, not astrocytic, tau burden and lacked aging-related tau astrogliopathy data; contribution of primary age-related tauopathy or AD subtypes was unknown; only single-epitope fibrillary Aβ and helical filament tau were quantified; and autopsy was limited to one hemisphere.
  • Evident from the text: the cross-sectional autopsy design cannot establish causality or temporal ordering, and the cohort composition may limit generalizability to more diverse or clinically referred populations.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00401-018-1920-1

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

20 of 42 cited sources checked · 13 supported · 3 flagged · accuracy not yet measured

  • Premisecitation

    Two studies that reported different sex-AD pathology association in different ages did not utilize statistical interaction modeling.

    “Likewise, two studies that reported different sex-AD pathology association in different ages did not utilize statistical interaction modeling [34,43].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [34] Kovacs GG, Alafuzoff I, Al-Sarraj S, Arzberger T, Bogdanovic N, Capellari S et al (2008) Mixed brain pathologies in dementia: the BrainNet Europe consortium experience. Dement Geriatr Cogn Disord 26:343–350 source
    • cites [43] Nelson PT, Schmitt FA, Jicha GA, Kryscio RJ, Abner EL, Smith CD et al (2010) Association between male gender and cortical Lewy body pathology in large autopsy series. J Neurol 257:1875–1881 source

      The Results (page not provided) report a different sex–AD pathology association before and after age 80, but they also state that an age-by-diagnosis interaction was assessed in a separate logistic model. That directly contradicts the claim that this study did not use statistical interaction modeling; the interaction was not significant. (LLM, conf=0.92)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Study design and conductreasoning

    The two cohorts (ROS and MAP) used uniform data collection, making it feasible to combine data across them to examine associations of clinical data with brain pathologies.

    “With uniform data collection, it is feasible to combine data across the two cohorts to examine associations of clinical data with brain pathologies, as done in many of our prior studies [4,45].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [4] Arvanitakis Z, Capuano AW, Leurgans SE, Bennett DA, Schneider JA (2016) Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol 15:934–943 source
    • cites [45] Oveisgharan S, Buchman AS, Yu L, Farfel J, Hachinski V, Gaiteri C et al (2018) APOE epsilon2epsilon4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults. Neurology 92(24):e2127–e2134 source
  • Premisecitation

    Clinical longitudinal studies have shown susceptibility of women with surgical menopause at young ages to cognitive decline and dementia.

    “Yet, clinical longitudinal studies have shown susceptibility of women with surgical menopause at young ages to cognitive decline [14] and dementia [52].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [14] Bove R, Secor E, Chibnik LB, Barnes LL, Schneider JA, Bennett DA et al (2014) Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology 82:222–229 source
    • cites [52] Rocca WA, Grossardt BR, Shuster LT, Stewart EA (2012) Hysterectomy, oophorectomy, estrogen, and the risk of dementia. Neurodegener Dis 10:175–178 source
  • Premisecitation

    In a previous study, younger age at onset of menopause among women with surgical, not natural, menopause was associated with more AD pathologies.

    “In our previous study, we found that younger age at onset of menopause among women with surgical, not natural, menopause was associated with more AD pathologies [14].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Bove R, Secor E, Chibnik LB, Barnes LL, Schneider JA, Bennett DA et al (2014) Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology 82:222–229 source
  • Premisecitation

    Few if any previous studies that investigated the association of sex with AD pathologies have examined menopausal factors.

    “Few if any of the previous studies which investigated the association of sex with AD pathologies have examined menopausal factors [25,41,43,53].”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [25] Hohman TJ, Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B et al (2018) Sex-specific association of apolipoprotein E With cerebrospinal fluid levels of Tau. JAMA Neurol 75(8):989–998 source

      The Introduction describes prior research on sex differences in APOE-associated Alzheimer’s pathology, and the Discussion proposes hormonal changes around menopause as a possible mechanism. Neither passage says whether few, if any, previous studies examined menopausal factors. Searches for menopausal status and hormone measures did not establish that claim. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [41] Miller FD, Hicks SP, D’Amato CJ, Landis JR (1984) A descriptive study of neuritic plaques and neurofibrillary tangles in an autopsy population. AmJ Epidemiol 120:331–341 source
    • cites [43] Nelson PT, Schmitt FA, Jicha GA, Kryscio RJ, Abner EL, Smith CD et al (2010) Association between male gender and cortical Lewy body pathology in large autopsy series. J Neurol 257:1875–1881 source

      The Introduction and Discussion discuss sex hormones as possible influences on neurodegenerative disease, but do not assess whether previous studies of sex and AD pathology examined menopausal factors. A search for menopause, postmenopausal status, and related factors found only a postmenopausal-estrogen study in the References, not a statement supporting the claimed assessment of prior studies. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [53] Sandberg G, Stewart W, Smialek J, Troncoso JC (2001) The prevalence of the neuropathological lesions of Alzheimer’s disease is independent of race and gender. Neurobiol Aging 22:169–175 source
  • Classified as probably not a substantial claim. 24
  • May combine two claims. 29

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The 4-stage classification of TDP-43 distribution was based on previous studies.

    “In this study, we used a 4-stages classification of TDP-43 distribution based on previous studies [30,42]”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [30] James BD, Wilson RS, Boyle PA, Trojanowski JQ, Bennett DA, Schneider JA (2016) TDP-43 stage, mixed pathologies, and clinical Alzheimer’s-type dementia. Brain 139:2983–2993 source
    • cites [42] Nag S, Yu L, Capuano AW, Wilson RS, Leurgans SE, Bennett DA et al (2015) Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease. Ann Neurol 77:942–952 source

      The Methods (Immunohistochemical studies) explicitly recognize three stages of TDP-43 distribution, not four. The paper says its assessment was described previously, but it does not support the attributed four-stage classification. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Only a few studies have directly investigated the association between sex and AD and other common neuropathologies, and these had small sample sizes (less than 200 brain autopsies) or did not examine pathologies other than AD.

    “Yet, to date, only a few studies have directly investigated the association between sex and AD and other common neuropathologies. Further, these included only a small sample size (less than 200 brain autopsies) [41,53], or did not examine pathologies other than AD [41,43,53].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [41] Miller FD, Hicks SP, D’Amato CJ, Landis JR (1984) A descriptive study of neuritic plaques and neurofibrillary tangles in an autopsy population. AmJ Epidemiol 120:331–341 source
    • cites [53] Sandberg G, Stewart W, Smialek J, Troncoso JC (2001) The prevalence of the neuropathological lesions of Alzheimer’s disease is independent of race and gender. Neurobiol Aging 22:169–175 source
    • cites [43] Nelson PT, Schmitt FA, Jicha GA, Kryscio RJ, Abner EL, Smith CD et al (2010) Association between male gender and cortical Lewy body pathology in large autopsy series. J Neurol 257:1875–1881 source

      The paper contradicts the characterization attributed to it. Its Abstract reports 3,830 autopsied subjects, and the Introduction says it tested associations between sex and AD, neocortical Lewy body, and mixed pathologies—not AD alone. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Another study reported that an AD pathologic diagnosis was more common among women in patients older than age 75 years.

    “Further, another study reported that an AD pathologic diagnosis was more common among women in patients older than age 75 years [34].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] Kovacs GG, Alafuzoff I, Al-Sarraj S, Arzberger T, Bogdanovic N, Capellari S et al (2008) Mixed brain pathologies in dementia: the BrainNet Europe consortium experience. Dement Geriatr Cogn Disord 26:343–350 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Common age-related neuropathologies, including Alzheimer's disease and other neurodegenerative and cerebrovascular pathologies, are the main causes of dementia, including Alzheimer's dementia.

    “Common age-related neuropathologies, including Alzheimer’s disease (AD) and other neurodegenerative and cerebrovascular pathologies, are the main causes of dementia, including Alzheimer’s dementia [31,34].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [31] Jellinger KA, Attems J (2015) Challenges of multimorbidity of the aging brain: a critical update. J Neural Transm (Vienna) 122:505–521 source
    • cites [34] Kovacs GG, Alafuzoff I, Al-Sarraj S, Arzberger T, Bogdanovic N, Capellari S et al (2008) Mixed brain pathologies in dementia: the BrainNet Europe consortium experience. Dement Geriatr Cogn Disord 26:343–350 source

      The Introduction says neurodegenerative diseases are the most common disorders underlying dementia, and the Results document AD, vascular pathology, and other diagnoses among people with dementia. The Influence of Age and Gender section reports that AD and combined diagnoses were more frequent in older patients. The paper does not establish that cerebrovascular pathology is among the main causes, or specifically assess the causes of clinically diagnosed Alzheimer’s dementia. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In prior work, women who had surgical menopause at an early age had a faster decline in cognitive function and more AD pathology at autopsy, and neuritic plaques in particular, compared to women with surgical menopause at older ages.

    “In prior work, we found that women, a subset of those in the current study, who had surgical menopause at an early age had a faster decline in cognitive function and more AD pathology at autopsy, and neuritic plaques in particular, compared to women with surgical menopause at older ages [14].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Bove R, Secor E, Chibnik LB, Barnes LL, Schneider JA, Bennett DA et al (2014) Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology 82:222–229 source

  • May combine two claims.

    Premisecitation

    One clinical-pathologic study reported that the odds of AD pathology was not different between women and men if they were younger than 80 years at death, but women older than 80 years had a higher odds of AD pathology compared to men.

    “One clinical-pathologic study reported that the odds of AD pathology was not different between women and men if they were younger than 80 years at death, but women older than 80 years had a higher odds of AD pathology compared to men [43].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [43] Nelson PT, Schmitt FA, Jicha GA, Kryscio RJ, Abner EL, Smith CD et al (2010) Association between male gender and cortical Lewy body pathology in large autopsy series. J Neurol 257:1875–1881 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Vascular risk factors like higher blood pressure levels are associated with cerebral vessel disease including arteriolosclerosis.

    “while vascular risk factors like higher blood pressure levels have been found associated with cerebral vessel disease including arteriolosclerosis [28,3]”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [28] Ighodaro ET, Abner EL, Fardo DW, Lin AL, Katsumata Y, Schmitt FA et al (2017) Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals. J Cereb Blood Flow Metab 37:201–216 source
    • cites [3] Arvanitakis Z, Capuano AW, Lamar M, Shah RC, Barnes LL, Bennett DA et al (2018) Late-life blood pressure association with cerebrovascular and Alzheimer disease pathology. Neurology. https://doi.org/10.1212/wnl.0000000000005951 source

  • May combine two claims.

    Findingown data

    More than 60% of all autopsied participants met criteria for a pathologic diagnosis of AD, and the percentage was higher among women (68%) than men (58%) (p<0.001).

    “More than 60% of all autopsied participants met criteria for a pathologic diagnosis of AD, and the percentage was higher among women (68%) than men (58%) (p<0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Participants older than 90 were not different from participants aged 80-90 years in global AD pathologic scores (p=0.238), but both groups had higher scores than participants younger than 80 (both p<0.001), indicating a non-linear relationship between age and AD pathology.

    “However, participants older than 90 were not different from participants aged 80–90 years (p = 0.238) although both groups had higher global AD pathologic scores than participants younger than 80 (both p < 0.001), indicating a non-linear relationship between age and AD pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared to men, women were less likely to have gross infarcts (OR=0.78, 95% CI:0.61-0.98, p=0.037), although the association was attenuated after controlling for vascular risk factors.

    “and less likely to have gross infarcts (OR=0.78, 95% CI:0.61–0.98, p=0.037), although the association with gross infarct was attenuated after controlling for vascular risk factors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Women had higher levels of tangles in both mesial temporal and neocortical regions, but had higher levels of amyloid only in the mesial temporal.

    “Women had higher levels of tangles in both mesial temporal and neocortical regions, but had higher levels of amyloid only in the mesial temporal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Women were about 3 years older than men (p<0.001), had one year less of education (p<0.001), and had fewer vascular risk factors (p<0.001).

    “Women were about 3 years older than men (p<0.001), had one year less of education (p<0.001), and had fewer vascular risk factors (p<0.001).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    HRT was used by nearly 40% (n=397) of women in their life, was more frequently used by women with surgical than natural menopause (59% vs. 33%, p<0.001), and was in the oral dosing formulation in 93% of women.

    “HRT was used by nearly 40% (n=397) of women in their life, was more frequently used by women with surgical than natural menopause (59% vs. 33%, p<0.001), and was in the oral dosing formulation in 93% of women.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both women with natural menopause and women with surgical menopause have higher levels of AD pathologies compared to men.

    “We found that both women with natural and those with surgical menopause have higher levels of AD pathologies compared to men.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    About a third of women (n=306, 32%) reported having been exposed to surgical menopause, and menopause was induced by hysterectomy in 95% of cases.

    “About a third of women (n=306, 32%) reported having been exposed to surgical menopause, and menopause was induced by hysterectomy in 95% of cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was no sex difference in APOE ε4 status (p=0.844), Alzheimer's dementia (p=0.099), or vascular diseases burden (p=0.633).

    “We did not observe any sex difference in the APOE ε4 status (p=0.844), Alzheimer’s dementia (p=0.099), or vascular diseases burden (p=0.633).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Compared to women with natural menopause, women with surgical menopause were younger at menopause (43.4±7.7 vs.48.8±5.5, p<0.001), but were not different at age of death (89.6±6.3 vs. 90.0±6.7, p=0.350) or years of education (15.7±3.4 vs. 15.9±3.3, p=0.458).

    “Compared to women with natural menopause, women with surgical menopause were younger at menopause (43.4±7.7 vs.48.8±5.5, p<0.001), as expected, but were not different at age of death (89.6±6.3 vs. 90.0±6.7, p=0.350) or years of education (15.7±3.4 vs. 15.9±3.3, p=0.458).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In ROS, 93% of deceased participants had an autopsy.

    “Of 732 (93%) who had an autopsy”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The overall follow-up rate of both cohorts exceeds 90%, and the autopsy rate exceeds 85%.

    “The overall follow-up rate of both cohorts exceeds 90%, and the autopsy rate exceeds 85%.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    In earlier work, women had more AD pathology and neurofibrillary tangles in particular, but not neuritic or diffuse plaques, among 141 subjects who came to autopsy.

    “Also, in earlier work, we found that women had more AD pathology and neurofibrillary tangles in particular, but not neuritic or diffuse plaques, among 141 subjects who came to autopsy [8].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, Bennett DA (2005) Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry 62:685–691 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Another study reported that the association of APOE ε4 with neurofibrillary tangles was weaker in men than in women, while the association with senile plaques was significant in both sexes.

    “and another study reported that the association of APOE ε4 with neurofibrillary tangles was weaker in men than in women, while the association with senile plaques was significant in both sexes [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Ghebremedhin E, Schultz C, Thal DR, Rub U, Ohm TG, Braak E et al (2001) Gender and age modify the association between APOE and AD-related neuropathology. Neurology 56:1696–1701 source

  • May combine two claims.

    Study design and conductcitation

    The regional standardized scores were highly correlated with the global AD pathology score (r range 0.47-0.73, median 0.67) and Chronbach α 0.90, supporting use of the global AD pathology score.

    “In our previous study, we showed that the regional standardized scores were highly correlated with the global AD pathology score (r range: 0.47–0.73, median r = 0.67) and the Chronbach α coefficient was 0.90, indicating high internal consistency and supporting use of the global AD pathology score [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Bennett DA, Wilson RS, Schneider JA, Evans DA, Aggarwal NT, Arnold SE et al (2003) Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer’s disease. Neurology 60:246–252 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    One autopsy study found that women had more senile plaques, and the association was stronger among ε4 carriers.

    “One autopsy study found that women had more senile plaques, and the association was stronger among ε4 carriers [17]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Corder EH, Ghebremedhin E, Taylor MG, Thal DR, Ohm TG, Braak H (2004) The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions: modification by age, sex, and APOE polymorphism. Ann N Y Acad Sci 1019:24–28 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The dichotomous summary variable for neocortical-type Lewy body pathology was previously shown to be associated with dementia.

    “In this study, a dichotomous summary variable was used indicative of presence or absence of neocortical-type Lewy body pathology which we previously showed to be associated with dementia [57].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Schneider JA, Arvanitakis Z, Yu L, Boyle PA, Leurgans SE, Bennett DA (2012) Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies. Brain 135:3005–3014 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Of the estimated 5.2 million people with Alzheimer's dementia in the United States, 3.3 million are women and 1.9 million are men.

    “Of the estimated 5.2 million people with Alzheimer’s dementia in the United States, 3.3 million are women and 1.9 million are men [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Association Alzheimer’s (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12:459–509 source

  • May combine two claims.

    Study design and conductcitation

    The summary measures of tau tangle density and Aβ load were reliable and internally consistent, with Chronbach α 0.84 for tangles and 0.88 for Aβ.

    “In our previous paper, we showed these summary measures to be reliable and internally consistent [11]. The Chronbach α coefficient was 0.84 for the tangles densities and 0.88 for the Aβ loads, showing high item (regions’ measures) total (summary measures) correlations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE (2004) Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol 61:378–384 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    DNA genotyping was performed by investigators blinded to all clinical and pathological data.

    “DNA genotyping was performed at Polymorphic DNA Technologies (Alameda, CA) by investigators blinded to all clinical and pathological data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In MAP, 83% of deceased participants had an autopsy.

    “of whom 756 (83%) had an autopsy”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    A board-certified neuropathologist, blinded to clinical data, determined the pathologic diagnosis of AD based on published criteria.

    “In addition, a board-certified neuropathologist, blinded to clinical data, determined the pathologic diagnosis of AD based on published criteria [26].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Hyman BT, Trojanowski JQ (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 56:1095–1097 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Core models were evaluated for violations of assumptions, by examining data both analytically and graphically.

    “Core models were evaluated for violations of assumptions, by examining data both analytically and graphically.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Adding terms for other common brain pathologies to the core models did not change the results: women had more AD pathology, specifically more tau tangles density.

    “We added terms for other common brain pathologies to the predictors of the core models, and the results did not change: women had more AD pathology, specifically more tau tangles density (Supplemental Table e-6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Participants had higher levels of education and more than 95% were Caucasians, reducing generalizability to other populations.

    “Participants had higher levels of education and more than 95% were Caucasians, reducing generalizability to other populations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    More advanced statistical methods and larger samples may explain the discrepant results among recent and prior studies.

    “More advanced statistical methods and larger samples may explain the discrepant results among recent and prior studies.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Neuropathological evaluations were conducted blinded to clinical data.

    “Finally, the two studies have uniform and structured procedures, and neuropathological evaluations are conducted blinded to clinical data.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The authors do not know how much of their tangle finding was driven by primary age-related tauopathy (PART), or what subtypes of AD account for most of the variance in the association of sex with the AD pathologic indices.

    “Also, we do not know how much of our tangle finding was driven by the primary age-related tauopathy (PART), or what subtypes of AD, i.e. tangle-predominant form of AD, account for most of the variance in the association of sex with the AD pathologic indices.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Two other studies reported differential associations between APOE ε4 and AD pathological indices in women and men, but they did not contain a formal interaction test between sex and APOE ε4.

    “Although two other studies reported differential associations between APOE ε4 and AD pathological indices in women and men [17,24], they do not contain any formal interaction test between sex and APOE ε4.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Corder EH, Ghebremedhin E, Taylor MG, Thal DR, Ohm TG, Braak H (2004) The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions: modification by age, sex, and APOE polymorphism. Ann N Y Acad Sci 1019:24–28 source
    • cites [24] Ghebremedhin E, Schultz C, Thal DR, Rub U, Ohm TG, Braak E et al (2001) Gender and age modify the association between APOE and AD-related neuropathology. Neurology 56:1696–1701 source

  • May combine two claims.

    Interpretationreasoning

    Taken together, menopausal factors did not account for the higher AD pathology, and tau specifically, among women.

    “Taken together, menopausal factors did not account for the higher AD pathology, and tau specifically, among women.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The authors currently do not have data on aging-related tau astriogliopathy (ARTAG).

    “Our tau tangle density measure describes only neuronal, not astrocytic, tau tangle burden, and currently we do not have data on aging-related tau astriogliopathy (ARTAG).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The autopsy procedures were carried out on only one hemisphere, and pathologies restricted to the other hemisphere may be missed.

    “Lastly, the autopsy procedures were carried out on only one hemisphere, and pathologies restricted to the other hemisphere may be missed.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The two studies have uniform and structured procedures.

    “Finally, the two studies have uniform and structured procedures, and neuropathological evaluations are conducted blinded to clinical data.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The study included about 1500 brain autopsies of participants in one of two community-based longitudinal studies of ageing, with a large proportion of women allowing for comparison of women and men.

    “It included about 1500 brain autopsies of participants in one of two community-based longitudinal studies of ageing, and with a large proportion of women allowing for comparison of women and men.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The authors only quantified the helical filament tau-positive tangles and the fibrillary form of Aβ by utilizing antibodies against single epitopes.

    “Furthermore, we only quantified the helical filament tau-positive tangles and the fibrillary form of Aβ by utilizing antibodies against single epitopes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A recent meta-analysis of 58,000 participants showed that APOE ε3/ε4 women have the same increased odds of AD dementia as APOE ε3/ε4 men, whereas a previous meta-analysis reported APOE ε4 women to carry a higher risk of Alzheimer's dementia compared to APOE ε4 men.

    “Furthermore, a recent meta-analysis of 58000 participants showed that APOE ε3/ε4 women have the same increased odds of AD dementia as APOE ε3ε4 men have, in contrast to a previous meta-analysis which reported APOE ε4 women to carry a higher risk of Alzheimer’s dementia compared to APOE ε4 men [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R et al (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer disease meta analysis consortium. JAMA 278:1349–1356 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The tau tangle density measure describes only neuronal, not astrocytic, tau tangle burden.

    “Our tau tangle density measure describes only neuronal, not astrocytic, tau tangle burden, and currently we do not have data on aging-related tau astriogliopathy (ARTAG).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The cohort studies have more than 90% follow up and about 85% autopsy rates, decreasing several sources of bias, including selection bias due to attrition.

    “Also, the cohort studies have more than 90% follow up and about 85% autopsy rates, decreasing several sources of bias, including selection bias due to attrition.”
    Quote in the paperSubstantial claim
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Authors
Oveisgharan, S., Arvanitakis, Z., Yu, L., Farfel, J., Schneider, J. A., & Bennett, D. A.
Affiliations
Rush University Medical Center (US)
Corresponding author
Oveisgharan, Shahram
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2018-10-17
Volume
136
Issue
6
Pages
887-900
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-018-1920-1
PMC
PMC6279593
OpenAlex
W2897712355
Semantic Scholar
1ad7c3913ad11214ddf4ab763a09c0c3f7cd5c6f
Cited by
330
References
67
Citations by year
2026: 37 · 2025: 69 · 2024: 43 · 2023: 47 · 2022: 44 · 2021: 42 · 2020: 23 · 2019: 23 · 2018: 2
FWCI
15.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
National Institutes of Health (R01AG17917, P30AG10161, RO1NS084965, R01AG15819)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
Keywords
Alzheimer's disease, sex differences, tau tangles, amyloid-beta, arteriolosclerosis, cerebral amyloid angiopathy, Lewy bodies, TDP-43, hippocampal sclerosis, cerebral infarction, atherosclerosis, postmortem brain examination, Religious Orders Study, Rush Memory and Aging Project
MeSH terms
Aged, Aged, 80 and over, Aging, Alzheimer Disease, Autopsy, Brain, Cross-Sectional Studies, DNA-Binding Proteins, Female, Humans, Longitudinal Studies, Male, Sex Characteristics, Chi-Square Distribution, tau Proteins, Arteriolosclerosis, alpha-Synuclein, Apolipoprotein E4

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