Higher Rates of Decline for Women and Apolipoprotein E Epsilon4 Carriers

Overview

Journal AJNR Am J Neuroradiol

Specialty Neurology

Date 2013 Jul 6

PMID 23828104

Citations 92

Authors

D Holland

R S Desikan

A M Dale

L K McEvoy

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Age and the apolipoprotein E ε4 allele are well-known risk factors for Alzheimer disease, but whether female sex is also a risk factor remains controversial. It is also unclear how these risk factors affect rates of structural brain and clinical decline across the spectrum of preclinical to clinical Alzheimer disease. Our objective is to estimate the effects of apolipoprotein E ε4 and sex on age-specific rates of morphometric and clinical decline in late-onset sporadic Alzheimer disease.

Materials And Methods: With the use of linear mixed-effects models, we examined the effect of age, apolipoprotein E ε4, and sex on longitudinal brain atrophy and clinical decline among cognitively normal older individuals and individuals with mild cognitive impairment and Alzheimer disease (total = 688). We also evaluated the relationship between these effects and CSF biomarkers of Alzheimer disease pathology.

Results: Apolipoprotein E ε4 significantly accelerated rates of decline, and women in all cohorts had higher rates of decline than men. The magnitude of the sex effect on rates of decline was as large as those of ε4, yet their relationship to measures of CSF biomarkers were weaker.

Conclusions: These results indicate that in addition to apolipoprotein E ε4 status, diagnostic and therapeutic strategies should take into account the effect of female sex on the Alzheimer disease process.

Citing Articles

Synaptic vulnerability to amyloid-β and tau pathologies differentially disrupts emotional and memory neural circuits.

Capilla-Lopez M, Deprada A, Andrade-Talavera Y, Martinez-Gallego I, Coatl-Cuaya H, Sotillo P Mol Psychiatry. 2025; .

PMID: 39885298 DOI: 10.1038/s41380-025-02901-9.

and Chronic Health Risk Factors are Associated with Sex-Specific Preclinical Alzheimer's Disease Neuroimaging Biomarkers.

Losinski G, Key M, Vidoni E, Clutton J, Morris J, Burns J medRxiv. 2024; .

PMID: 39606325 PMC: 11601779. DOI: 10.1101/2024.11.21.24317732.

Sex-specific risk factors and clinical dementia outcomes for white matter hyperintensities in a large South Korean cohort.

Schweitzer N, Son S, Thurston R, Li J, Chen C, Aizenstein H Alzheimers Res Ther. 2024; 16(1):243.

PMID: 39482724 PMC: 11529246. DOI: 10.1186/s13195-024-01598-2.

Sex/gender effects of glial reactivity on preclinical Alzheimer's disease pathology.

Vila-Castelar C, Akinci M, Palpatzis E, Aguilar-Dominguez P, Operto G, Kollmorgen G Mol Psychiatry. 2024; .

PMID: 39384963 DOI: 10.1038/s41380-024-02753-9.

Sex and Gender Differences in Alzheimer's Disease: Genetic, Hormonal, and Inflammation Impacts.

Kolahchi Z, Henkel N, Eladawi M, Villarreal E, Kandimalla P, Lundh A Int J Mol Sci. 2024; 25(15).

PMID: 39126053 PMC: 11313277. DOI: 10.3390/ijms25158485.

References

Folstein M, Folstein S, McHugh P . "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12(3):189-98. DOI: 10.1016/0022-3956(75)90026-6. View

Corder E, Ghebremedhin E, Taylor M, Thal D, Ohm T, Braak H . The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions: modification by age, sex, and APOE polymorphism. Ann N Y Acad Sci. 2004; 1019:24-8. DOI: 10.1196/annals.1297.005. View

Williams M, Storandt M, Roe C, Morris J . Progression of Alzheimer's disease as measured by Clinical Dementia Rating Sum of Boxes scores. Alzheimers Dement. 2012; 9(1 Suppl):S39-44. PMC: 3660405. DOI: 10.1016/j.jalz.2012.01.005. View

Xu H, Gouras G, Greenfield J, Vincent B, Naslund J, Mazzarelli L . Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med. 1998; 4(4):447-51. DOI: 10.1038/nm0498-447. View

Corder E, Saunders A, Strittmatter W, Schmechel D, Gaskell P, Small G . Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993; 261(5123):921-3. DOI: 10.1126/science.8346443. View

Seshadri S, Wolf P, Beiser A, Au R, McNulty K, White R . Lifetime risk of dementia and Alzheimer's disease. The impact of mortality on risk estimates in the Framingham Study. Neurology. 1997; 49(6):1498-504. DOI: 10.1212/wnl.49.6.1498. View

Plassman B, Langa K, Fisher G, Heeringa S, Weir D, Ofstedal M . Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology. 2007; 29(1-2):125-32. PMC: 2705925. DOI: 10.1159/000109998. View

Holland D, McEvoy L, Desikan R, Dale A . Enrichment and stratification for predementia Alzheimer disease clinical trials. PLoS One. 2012; 7(10):e47739. PMC: 3474753. DOI: 10.1371/journal.pone.0047739. View

Andersen K, Launer L, Dewey M, Letenneur L, Ott A, Copeland J . Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group. Neurology. 1999; 53(9):1992-7. DOI: 10.1212/wnl.53.9.1992. View

10.

Breitner J, Wyse B, Anthony J, Welsh-Bohmer K, Steffens D, Norton M . APOE-epsilon4 count predicts age when prevalence of AD increases, then declines: the Cache County Study. Neurology. 1999; 53(2):321-31. DOI: 10.1212/wnl.53.2.321. View

11.

Arriagada P, Marzloff K, Hyman B . Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease. Neurology. 1992; 42(9):1681-8. DOI: 10.1212/wnl.42.9.1681. View

12.

Growdon J, Locascio J, Corkin S, Gomez-Isla T, Hyman B . Apolipoprotein E genotype does not influence rates of cognitive decline in Alzheimer's disease. Neurology. 1996; 47(2):444-8. DOI: 10.1212/wnl.47.2.444. View

13.

Irvine K, Laws K, Gale T, Kondel T . Greater cognitive deterioration in women than men with Alzheimer's disease: a meta analysis. J Clin Exp Neuropsychol. 2012; 34(9):989-98. DOI: 10.1080/13803395.2012.712676. View

14.

Holland D, Dale A . Nonlinear registration of longitudinal images and measurement of change in regions of interest. Med Image Anal. 2011; 15(4):489-97. PMC: 3115407. DOI: 10.1016/j.media.2011.02.005. View

15.

Hyman B . Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch Neurol. 2011; 68(8):1062-4. DOI: 10.1001/archneurol.2011.70. View

16.

Sando S, Melquist S, Cannon A, Hutton M, Sletvold O, Saltvedt I . APOE epsilon 4 lowers age at onset and is a high risk factor for Alzheimer's disease; a case control study from central Norway. BMC Neurol. 2008; 8:9. PMC: 2375917. DOI: 10.1186/1471-2377-8-9. View

17.

JUVA K, Verkkoniemi A, Viramo P, Polvikoski T, Kainulainen K, Kontula K . APOE epsilon4 does not predict mortality, cognitive decline, or dementia in the oldest old. Neurology. 2000; 54(2):412-5. DOI: 10.1212/wnl.54.2.412. View

18.

Saunders A . Apolipoprotein E and Alzheimer disease: an update on genetic and functional analyses. J Neuropathol Exp Neurol. 2000; 59(9):751-8. DOI: 10.1093/jnen/59.9.751. View

19.

Farrer L, Cupples L, Haines J, Hyman B, Kukull W, Mayeux R . 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. 1997; 278(16):1349-56. View

20.

Murray M, Graff-Radford N, Ross O, Petersen R, Duara R, Dickson D . Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011; 10(9):785-96. PMC: 3175379. DOI: 10.1016/S1474-4422(11)70156-9. View