Sex differences in metabolic and vascular contributions to dementia.
April 30, 2020

Dr. Kristen Zuloaga is an Associate Professor of Neuroscience and Experimental Therapeutics (DNET) at Albany Medical College.  A list of her group’s recent publications can be found here:

(Her group has one of the best lab logos too!)

Her seminar focused on sex differences in metabolic and vascular contributions to dementia.

Dr. Zuloaga is interested in several different types of dementia, including classical forms of Alzheimer’s disease and vascular contributions to cognitive impairment and dementia (VCID).

She reminded us that dementias are very often the product of multiple pathologies.  About 60-80% of AD patients have vascular pathology.  This is called multi-etiology dementia.

By fortunate coincidence, Dr. Zuloaga’s seminar was presented one day after this article was published:

Montagne, A., Nation, D.A., Sagare, A.P. et al. APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature (2020).

So, clearly, there is increasing awareness that vascular pathology can be an important contributor to Alzheimer’s disease.

Dr. Zuloaga began by highlighting some basic sex-specific differences:

    • The risk of AD is higher for women.
    • The risk of VCID is higher for men, at least up to age 90.
    • Metabolic disease, especially diabetes at mid-life, is a risk factor for both.

She explained that her lab uses mouse models of AD to study sex differences in risk.

They examine the impact of a high fat (HF) diet which, as she reminded us, has a nutritional content similar to a double cheeseburger and triggers diabetes and hyperlipidemia in these mice.  This often results in cognitive decline in mice.

She observes that young female mice fed HF diets do not exhibit these problems.  They seem to be protected from the metabolic risks of a poor diet.

Graduate student Abby Salinero asked the question: is this “protection” is lost as female mice age?  To test this, she fed female mice of various ages a HF diet (vs a normal control diet; LF) for 3 months.  In young 6-week old mice, the females were indeed protected, and less impacted by the poor diet compared to male mice.  By early middle-age, however, the female mice had lost this protection; in fact, the female mice exhibited as many or more diet-related metabolic problems than the male mice.  Read more about this here:

Salinero, A.E., Anderson, B.M. & Zuloaga, K.L. Sex differences in the metabolic effects of diet-induced obesity vary by age of onset. Int J Obes 42, 1088–1091 (2018).

And here:

High-Fat Diet-Induced Obesity Causes Sex-Specific Deficits in Adult Hippocampal Neurogenesis in Mice.  Lisa S. Robison, Nathan M. Albert, Lauren A. Camargo, Brian M. Anderson, Abigail E. Salinero, David A. Riccio, Charly Abi-Ghanem, Olivia J. Gannon, Kristen L. Zuloaga.  eNeuro 23 December 2019, 7 (1) ENEURO.0391-19.2019; DOI: 10.1523/ENEURO.0391-19.2019

Dr. Zuloaga then expanded on this earlier work, by adding one more factor: reductions in brain blood flow that often co-occur with dementia (as in VCID).  She presented new data on how these three factors – sex, diet, and cerebral blood flow – interact to impact cognition.

To accomplish this she uses a surgical technique called cerebral hypoperfusion. This reduces blood flow to the right side of the brain by about 15% in mice, mimicking poor blood flow as it might occur with VCID.

Many of these experiments used the common 3xTg AD mouse model, a triple transgenic animal that develops both Aβ and p-tau pathology.

Here she highlighted several sets of experiments by Dr. Lisa Robinson, Olivia Gannon, and Febronia Mansour.  Together they examined the interactive impacts of poor blood flow, diet-induced metabolic disease, and sex on:

  • Brain blood flow
  • Glucose tolerance, and other markers of diabetes
  • Body mass, including visceral fat
  • Inflammatory markers
  • Behavior and cognition

In a series of experiments, they found that:

  • Both males and females had the expected reduction in blood flow in temporal cortical region.
  • The HF diet led to the expected weight gain; females had highest increase in visceral fat.
  • Males exhibited inflammation related to TNFα and IL-6.
  • Cognitive impairments were observed in mice subjected to HF diets, reduced cerebral blood flow (to mimic VCID), or the combination of both factors as detected in the:
    • Novel object recognition test
    • Morris water maze
    • Nest building assessment
  • Metabolic problems were generally linked to poorer cognitive performance.
  • Male and female mice had somewhat different responses, e.g. middle-age females were more effected by the HF diet than middle-age males.
  • The accumulation of visceral fat seemed to be especially problematic for females.
  • In general, middle-age female mice seemed to display more signs of metabolic problems and cognitive decline, compared to males.

Overall, the studies suggest that sex, poor diet, and reduced blood flow are all important risk factors for AD and related dementias.  These risk factors interact, in complex ways, to raise or lower risk.