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AlzRisk Risk Factor Literature Search Strategy and Results

Risk Factor: Hormone Therapy
  (postmenopausal hormone use)
Risk Factor Type: Medications
Current Understanding:
The tables on the Risk Factor Overview present results from a series of observational prospective studies and one randomized controlled trial of postmenopausal hormone therapy (including estrogen alone or in combination with progestin) in relation to AD risk. Overall, in contrast to earlier systematic reviews and meta-analyses, the evidence from these studies does not support benefits on AD risk. The relationship between postmenopausal hormone therapy and AD risk has been controversial; early observational studies, many of them retrospective, suggested a beneficial effect of hormone therapy, and randomized controlled trial results in postmenopausal women suggest that hormone therapy increases dementia risk, and also has adverse effects on other health outcomes. Confounding, as well as differences in the women’s ages, in the timing of use relative to menopause, and in hormone therapy formulation, may account for the disparate findings in earlier observational studies vs. subsequent clinical trials, but more recent observational studies suggest no benefit. Changes over time in the observational findings may be related to changes in hormone therapy use over time. In any case, estrogen remains one of the most effective treatments for relief from menopausal vasomotor symptoms, and, according to the North American Menopause Society, temporary use of hormone therapy may be appropriate to treat low-risk women with severe menopausal symptoms. For a discussion of the putative mechanisms by which hormone therapy may be related to AD risk and commentary on interpreting the findings below in a broader context, please see the Discussion. A longer review and discussion can be found in the closely related published review and meta-analysis, O'Brien J, Jackson JW, Grodstein F, Blacker D, Weuve J. Postmenopausal hormone therapy is not associated with risk of all-cause dementia and Alzheimer's Disease (Epidemiologic Reviews 2014;36:83-103).
Last Search Completed: 20 March 2014 - (Same date as last content update.)

Risk Factor Overview


We conducted our systematic literature search in the Medline (via PubMed and Ovid) and Embase databases through December 31, 2012. We used theMedline Medical Subject Headings (MeSH) database and the Embase EMTREE thesaurus, as well as relevant article abstracts and metadata, to compile lists of controlled vocabulary and free text terms that were incorporated into our search strategy. Our search terms included keywords for the exposure (e.g., “postmenopausal” or “hormone” or “estrogen”), the outcome(e.g., “Alzheimer”), and study design (e.g., “cohort” or “case-control”).

The search returned 2,046 citations from PubMed, Ovid Medline, and Embase; 526 duplicates were removed.We excluded 1,446 citations that did not meet our inclusion criteria (e.g., topic not appropriate, review or editorial, cross sectional or non-nested case-control study design), leaving 74 articles for full-text review. We then excluded 56 additional articles that did not meet the inclusion criteria, leaving 18 eligible peer-reviewed publications. We then excluded 3 articles that discussed WHIMS results published elsewhere in greater detail, 2 articles because they included results for all-cause dementia only, and 1 article because the study lacked systematic AD assessments for all participants. Thus, 12 articles are included in our Alzrisk review and tables.

We ran an update of the search in Pubmed on March 20, 2014. The new search (which covered articles published between December 31, 2012 and March 20, 2014) returned 21 new citations. We excluded 20 citations that did not meet our inclusion criteria (e.g., topic not appropriate, review or editorial, mouse studies). One study was excluded after full text review because it did not meet inclusion criteria. No articles were added to our Alzrisk tables from this updated search.

Search & Review Flowchart
Search Strategy
Selection of Papers Reporting on Data from the Same Cohort

Search Strategy Flowchart

Search Strategy

Using our systematic review methods, we developed a search strategy (table below) for Pubmed.

Search Strategy Table

Selection of Papers Reporting on Data from the Same Cohort

Some cohort studies produced multiple articles reporting on the association between alcohol use and risk for Alzheimer’s disease. To avoid presenting duplicate results, we reviewed such articles on a case-by-case basis and selected the most informative article(s) based on sample size, follow-up time, exposure assessment or modeling, and appropriateness of analytic methods.

For each cohort listed below, we cite the duplicative articles we reviewed and give our rationale for their inclusion or exclusion. The full citation for each article is provided in the reference section.

Cache County

We included both Zandi 2002 and Shao 2012 because they reported on different lengths of follow-up time, and categorized HT exposure in different ways. Zandi 2002 followed participants for an average of three years, while Shao 2012 followed participants for an average of seven years. Zandi 2002 reported on any v. no HT use, duration of use (< 3y, 3 – 10y, > 10y), and current v. former HT use (current v. former also broken down by duration: <3y, 3-10y, >10y). Shao 2012 included comparisons for time between menopause and HT initiation as well as HT formulation.

Rochester Epidemiology Project

We included both Waring 1999 and Roberts 2006 because they reported findings from different follow-up periods. Waring 1999 includes women who developed AD between 1980 and 1984, while Roberts 2006 includes women who developed AD between 1985 and 1989. Furthermore, the two studies report results for different categorizations of HT use. Waring 1999 reported findings for duration of HT use( 6 months, ≥ 6 months) v. minimal HT, as well as cumulative dose (0 mg, ≤ 20 mg, 21-500 mg, > 500 mg). Roberts 2006 included results for duration of use (never, 0.5-3 years, > 3 years), total cumulative dose (never, ≤ 756 mg, > 756 mg), age at initiation (never, ≤ 49.5 years, > 49.5 years), and time between menopause of HT initiation (never, ≤ 2 years, > 2 years).


Roberts RO, Cha RH, Knopman DS, Petersen RC, Rocca WA. Postmenopausal estrogen therapy and Alzheimer disease: overall negative findings. Alzheimer Dis Assoc Disord. 2006;20(3):141-146.

Shao H, Breitner JCS, Whitmer, et al. Hormone therapy and Alzheimer disease dementia: New findings from the Cache County Study. Neurology. 2012;79;1846-1852.

Waring SC, Rocca WA, Petersen RC, O'Brien PC, Tangalos EG, Kokmen E. Postmenopausal estrogen replacement therapy and risk of AD: a population-based study. Neurology. 1999;52(5):965-970.

Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA. 2002;288(17):2123-2129.