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

In the paper

“In this study, we used a 4-stages classification of TDP-43 distribution based on previous studies [30,42]”

What the sources say

• Supported

  The Pathological TDP-43 inclusions section says the authors created stages of TDP-43 distribution guided by prior literature and observations in their cohort. The Discussion explicitly calls it a four-stage scheme, including the stage with no TDP-43, and relates its progression to previous staging research. (LLM, conf=0.93)

  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
• Disputed

  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.

  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 sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• Disputed

  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.

  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 sourceExperimental — accuracy not yet measured

In the paper

“Further, another study reported that an AD pathologic diagnosis was more common among women in patients older than age 75 years [34].”

What the sources say

• Supported

  The “Influence of Age and Gender” section reports that among patients above 75, more women had pure AD. The Discussion likewise says the female predominance in neuropathologically diagnosed AD generally applied only above age 75. (LLM, conf=0.94)

  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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [31] Jellinger KA, Attems J (2015) Challenges of multimorbidity of the aging brain: a critical update. J Neural Transm (Vienna) 122:505–521 source
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Results section reports that younger age at surgical menopause was associated with faster global cognitive decline and a higher burden of AD neuropathology, with the strongest association among individual markers for neuritic amyloid plaques. The Neuropathologic measures section confirms that the pathology was assessed from brain autopsies. Page numbers were not supplied in our copy. (LLM, conf=0.94)

  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

In the paper

“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].”

What the sources say

• Supported

  The Abstract reports higher odds of AD pathology in women who died after age 80 and says this tendency was not seen before age 80. The Results likewise report a female tendency after 80 but no gender-related effect before 80. (LLM, conf=0.94)

  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

In the paper

“while vascular risk factors like higher blood pressure levels have been found associated with cerebral vessel disease including arteriolosclerosis [28,3]”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Supported

  In “Relation of BP to cerebrovascular disease pathology,” the paper reports that higher mean systolic blood pressure was associated with greater severity of both atherosclerosis and arteriolosclerosis. The Discussion likewise identifies these as large- and small-vessel pathologies. The association with arteriolosclerosis was specific to systolic, not diastolic, blood pressure. (LLM, conf=0.93)

  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

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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).”

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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).”

In the paper

“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).”

In the paper

“Of 732 (93%) who had an autopsy”

In the paper

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“One autopsy study found that women had more senile plaques, and the association was stronger among ε4 carriers [17]”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [2] Association Alzheimer’s (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12:459–509 source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“DNA genotyping was performed at Polymorphic DNA Technologies (Alameda, CA) by investigators blinded to all clinical and pathological data.”

In the paper

“of whom 756 (83%) had an autopsy”

In the paper

“In addition, a board-certified neuropathologist, blinded to clinical data, determined the pathologic diagnosis of AD based on published criteria [26].”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

“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).”

In the paper

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

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

“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).”

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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).”

In the paper

“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.”