Sex and age interact to determine clinicopathologic differences in Alzheimer’s disease

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Abstract

Women reportedly make up two-thirds of Alzheimer’s disease (AD) dementia sufferers. Many estimates regarding AD, however, are based on clinical series lacking autopsy confirmation. The Florida Autopsied Multi-Ethnic (FLAME) cohort was queried for AD cases with a total of 1625 identified ranging in age from 53 to 102 years at death. Standard neuropathologic procedures were employed and clinical information was retrospectively collected. Clinicopathologic and genetic data ( MAPT and APOE) were stratified by sex. Within the neuropathologically diagnosed AD cohort, the overall number of women and men did not differ. Men were younger at onset of cognitive symptoms, had a shorter disease duration, and more often had atypical (non-amnestic) clinical presentations. The frequency of autopsy-confirmed AD among women and men stratified by age at death revealed an inverse U-shaped curve in men and a U-shaped curve in women, with both curves having inflections at approximately 70 years of age. Regional counts of neurofibrillary tangles differed in women and men, especially when examined by age intervals. Women had overall greater severity of neurofibrillary tangle counts compared to men, especially in the hippocampus. Men were more often classified as hippocampal sparing AD, whereas limbic predominant AD was more common in women. Men and women did not differ in frequency of MAPT haplotype or APOE genotype. Atypical clinical presentations, younger age at onset and shorter disease duration were more frequent in men, suggesting that the lower reported frequency of AD in men may be due to more frequent atypical clinical presentations not recognized as AD. Our data suggest that neuropathologically diagnosed AD cases have the same frequency of women and men, but their clinical presentations and ages at onset tend to differ.

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Most cited references 21

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Prevalence of Dementia in the United States: The Aging, Demographics, and Memory Study

B.L. Plassman, K.M. Langa, G.G. Fisher … (2007)

Aim: To estimate the prevalence of Alzheimer’s disease (AD) and other dementias in the USA using a nationally representative sample. Methods: The Aging, Demographics, and Memory Study sample was composed of 856 individuals aged 71 years and older from the nationally representative Health and Retirement Study (HRS) who were evaluated for dementia using a comprehensive in-home assessment. An expert consensus panel used this information to assign a diagnosis of normal cognition, cognitive impairment but not demented, or dementia (and dementia subtype). Using sampling weights derived from the HRS, we estimated the national prevalence of dementia, AD and vascular dementia by age and gender. Results: The prevalence of dementia among individuals aged 71 and older was 13.9%, comprising about 3.4 million individuals in the USA in 2002. The corresponding values for AD were 9.7% and 2.4 million individuals. Dementia prevalence increased with age, from 5.0% of those aged 71–79 years to 37.4% of those aged 90 and older. Conclusions: Dementia prevalence estimates from this first nationally representative population-based study of dementia in the USA to include subjects from all regions of the country can provide essential information for effective planning for the impending healthcare needs of the large and increasing number of individuals at risk for dementia as our population ages.

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Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging.

R Petersen, R Roberts, D S Knopman … (2010)

We investigated the prevalence of mild cognitive impairment (MCI) in Olmsted County, MN, using in-person evaluations and published criteria. We evaluated an age- and sex-stratified random sample of Olmsted County residents who were 70-89 years old on October 1, 2004, using the Clinical Dementia Rating Scale, a neurologic evaluation, and neuropsychological testing to assess 4 cognitive domains: memory, executive function, language, and visuospatial skills. Information for each participant was reviewed by an adjudication panel and a diagnosis of normal cognition, MCI, or dementia was made using published criteria. Among 1,969 subjects without dementia, 329 subjects had MCI, with a prevalence of 16.0% (95% confidence interval [CI] 14.4-17.5) for any MCI, 11.1% (95% CI 9.8-12.3) for amnestic MCI, and 4.9% (95% CI 4.0-5.8) for nonamnestic MCI. The prevalence of MCI increased with age and was higher in men. The prevalence odds ratio (OR) in men was 1.54 (95% CI 1.21-1.96; adjusted for age, education, and nonparticipation). The prevalence was also higher in subjects who never married and in subjects with an APOE epsilon3epsilon4 or epsilon4epsilon4 genotype. MCI prevalence decreased with increasing number of years of education (p for linear trend <0.0001). Our study suggests that approximately 16% of elderly subjects free of dementia are affected by MCI, and amnestic MCI is the most common type. The higher prevalence of MCI in men may suggest that women transition from normal cognition directly to dementia at a later age but more abruptly.

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Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity.

Yong-Jie Zhang, Ya-Fei Xu, Casey Cook … (2009)

Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining histopathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a approximately 25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.

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Author and article information

Contributors

Melissa E. Murray:

ORCID: http://orcid.org/0000-0001-7379-2545

904-953-1083 , murray.melissa@mayo.edu

Journal

Journal ID (nlm-ta): Acta Neuropathol

Journal ID (iso-abbrev): Acta Neuropathol

Title: Acta Neuropathologica

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0001-6322

ISSN (Electronic): 1432-0533

Publication date (Electronic): 15 September 2018

Publication date PMC-release: 15 September 2018

Publication date (Print): 2018

Volume: 136

Issue: 6

Pages: 873-885

Affiliations

[1 ]ISNI 0000 0004 0443 9942, GRID grid.417467.7, Departments of Neuroscience, , Mayo Clinic, ; Jacksonville, FL 32224 USA

[2 ]ISNI 0000 0004 0443 9942, GRID grid.417467.7, Departments of and Neurology, , Mayo Clinic, ; Jacksonville, FL USA

[3 ]ISNI 0000 0004 0443 9942, GRID grid.417467.7, Biomedical Statistics and Informatics, , Mayo Clinic, ; Jacksonville, FL USA

[4 ]ISNI 0000 0004 0430 4458, GRID grid.410396.9, Wien Center for Alzheimer’s Disease and Memory Disorders, , Mount Sinai Medical Center, ; Miami Beach, FL USA

Author information

Melissa E. Murray http://orcid.org/0000-0001-7379-2545

Article

Publisher ID: 1908

DOI: 10.1007/s00401-018-1908-x

PMC ID: 6280837

PubMed ID: 30219939

SO-VID: 53890f65-52ac-4473-9f2d-98be873ccd73

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 18 May 2018

Date revision received : 8 September 2018

Date accepted : 9 September 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100006827, Florida Department of Health;

Award ID: 6AZ01

Award ID: 8AZ06

Award Recipient : Melissa E. Murray

Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;

Award ID: R01 AG054449

Award Recipient : Melissa E. Murray

Funded by: FundRef http://dx.doi.org/10.13039/100012292, Gerstner Family Foundation;

Award ID: Career Development Award

Award Recipient : Melissa E. Murray

Custom metadata

ScienceOpen disciplines: Neurology

Keywords: alzheimer’s disease,neuropathology,sex,gender,neurofibrillary tangle,atypical,plaques,age,young onset,late onset,autopsy,postmortem

Data availability:

ScienceOpen disciplines: Neurology

Keywords: alzheimer’s disease, neuropathology, sex, gender, neurofibrillary tangle, atypical, plaques, age, young onset, late onset, autopsy, postmortem

Sex and age interact to determine clinicopathologic differences in Alzheimer’s disease

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Most cited references 21

Prevalence of Dementia in the United States: The Aging, Demographics, and Memory Study

Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging.

Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity.

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