Sex Differences in the Clinical Manifestations of Alzheimer Disease Pathology

Barnes, Lisa L.; Wilson, Robert S.; Bienias, Julia L.; Schneider, Julie A.; Evans, Denis A.; Bennett, David A.

doi:10.1001/archpsyc.62.6.685

Cited by 504 publications

(415 citation statements)

References 49 publications

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“…Although the amount of AD pathology may not differ between men and women, recent evidence suggests that the relationship between pathology and clinical status may be gender specific. A one unit (as defined by Barnes et al, 2005) increase of AD pathology was associated with a 3-fold increase in the odds of clinical AD in men compared with a more than 20-fold increase in the odds of clinical AD in women (Barnes et al, 2005). Thus, the finding that female 3xTg-AD mice have increased cognitive deficits compared to male 3xTg-AD mice without differences in AD-related pathology is in accord with the aforementioned findings in humans.…”

Section: Discussionsupporting

confidence: 76%

Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice

Clinton

Billings

Green

et al. 2007

Neurobiology of Disease

265

205

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We sought to determine if sex impacts the cognitive and neuropathological phenotype of the 3xTg-AD mice. We find that male and female 3xTg-AD mice show comparable impairments on Morris water maze (MWM) and inhibitory avoidance (IA) at 4 months. Shortly thereafter, however, the cognitive performance varies among the sexes, with females performing worse than males. These behavioral differences are not attributable to differences in Aβ or tau levels. The behavioral effect is transient as from 12 months onward, the disparity is no longer apparent. Because females perform worse than males on stressful tasks, we explored their corticosterone responses, and find that young female 3xTg-AD mice show markedly heightened corticosterone response after 5 days of MWM training compared to age-matched male 3xTg-AD mice; this difference is no longer apparent in older mice. Thus, the enhanced corticosterone response of the young female mice likely underlies their poorer performance on stressful tasks.

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Section: Discussionsupporting

confidence: 76%

Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice

Clinton

Billings

Green

et al. 2007

Neurobiology of Disease

265

205

View full text Add to dashboard Cite

show abstract

“…Finally, a recent genome-wide association (GWA) study identified a highly significant correlation between single-nucleotide polymorphisms (SNPs) in the Reelin locus and protection against dementia in elderly with high NFT load in AD-vulnerable brain areas (Kramer et al, 2011). Moreover, Seripa and colleagues identified additional SNPs in the Reelin locus that were significantly associated with AD pathogenesis in women (Seripa et al, 2008), in agreement with the study showing that women have a higher risk for AD than men primarily related to the higher density of NFTs (Barnes et al, 2005). Since the identified SNPs are located mainly in CpG islands within the Reelin promoter (Chen et al, 2002), shown to undergo epigenetic modifications as a part of regulatory mechanism of LTP (Levenson et al, 2008, Sui et al, 2012, it would be of highest relevance to further confirm (Kramer et al, 2011) and to check if these SNPs (Seripa et al, 2008) are correlated with a significant increase or decrease of Reelin levels, respectively.…”

Section: And Promotessupporting

confidence: 55%

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

et al. 2013

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Alzheimer's disease (AD) is one of the largest unmet medical concerns of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles, the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiological characteristic of late-onset AD. AbstractAlzheimer`s disease (AD) is one of the largest unmet medical needs of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles (NFTs), the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiology characteristic of late-onset AD.3

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“…One may predict that the gender difference of the association of APN with AD may be attributed to a hormonal difference, as APN and estrogen are inversely correlated and APN is increased in postmenopausal women 14, 43. Alternatively, women are likely to have more cognitive impairment than men at the same level of neuropathology 14, 44. Thus, a gender difference characterizes the relationship of increased plasma APN, leading to neurodegeneration in women with AD.…”

Section: Apn May Increase Ad Riskmentioning

confidence: 99%

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

Waragai

Ho²,

Takamatsu

et al. 2017

Ann Clin Transl Neurol

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A recent study suggested that insulin resistance may play a central role in the pathogenesis of Alzheimer's disease (AD). In this regard, it is of note that upregulation of plasma adiponectin (APN), a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation, has recently been associated with the severities of amyloid deposits and cognitive deficits in the elderly, suggesting that APN may enhance the risk of AD. These results are unanticipated because AD has been linked to type II diabetes and other metabolic disorders in which hypoadiponectinemia has been firmly established, and because APN ameliorated neuropathological features in a mouse model of neurodegeneration. Therefore, the objective of this study is to discuss the possible mechanisms underlying the biological actions of APN in the context of AD. Given that insulin receptor signaling is required for normal function of the nervous system, we predict that APN may be upregulated to compensate for compromised activity of the insulin receptor signaling pathway. However, increased APN might be sequestered by tau in the brain, leading to neurotoxic protein aggregation in AD. Alternatively, misfolding of APN may result in downregulation of the insulin/APN signal transduction network, leading to decreased neuroprotective and neurotrophic activities. Thus, it is possible that both ‘gain of function’ and ‘loss of function’ of APN may underlie synaptic dysfunction and neuronal cell death in AD. Such a unique biological mechanism underlying APN function in AD may require a novel therapeutic strategy that is distinct from previous treatment for metabolic disorders.

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Sex Differences in the Clinical Manifestations of Alzheimer Disease Pathology

Abstract: These data suggest that AD pathology is more likely to be clinically expressed as dementia in women than in men.

Cited by 504 publications

References 49 publications

Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice

Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

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