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Ongoing research projects in the Pike Lab are using a range of rodent models, cell culture paradigms and analyses of human tissues both to investigate underlying factors in Alzheimer’s pathogenesis and to develop translatable approaches to prevent and treat the disease. Current investigations, outlined below, emphasize the interactive risks of obesity and depletion of sex steroid hormones as well as pursue two promising, novel therapeutic strategies.

Sex differences in AD risk associated with APOE4

APOE4, the primary genetic risk factor for Alzheimer’s disease (AD), causes a greater lifetime risk and an increased rate of cognitive decline in women compared to men. The reasons for this sex-based link remain unknown. Our collaborative team is investigating the novel hypothesis that normal developmental processes that underlie sexual differentiation yield a female brain that is inherently more vulnerable to the effects of APOE4. We are examining this hypothesis using both human twin populations and transgenic mice that harbor human APOE alleles and AD transgenes. The results of this research will provide essential information to address the critical need for treatment options for women at high risk for AD from APOE4.

Menopause, Obesity, and Alzheimer’s Disease

Menopause is characterized in part by depletion of the ovarian hormones. We hypothesize that menopause induces neural changes that attenuate the established protective effects of estradiol and progesterone against pathways associated with AD pathogenesis. Menopause is also linked with increases in body weight and adiposity that often lead to obesity and metabolic syndrome, conditions that are established risk factors for the development of AD. Significantly, adiposity and obesity are not only regulated by ovarian hormones, but also are known to impair bioenergetics and increase inflammation. Thus, perimenopause results in adverse changes to both ovarian hormones and adiposity, which we theorize interact cooperatively in the promotion on AD pathogenesis via their effects on bioenergetic, inflammatory, and AD pathways. Ongoing studies are defining how perimenopause and adiposity interact to cooperatively drive development of AD pathology using non-transgenic and transgenic rodent models.

Interactions among TREM2, APOE4, and sex

Alzheimer’s disease (AD) is characterized by significant sex differences that affect the vulnerability, clinical manifestation, and neuropathological progression of AD, often exhibiting a negative female bias. Indeed, the most significant genetic risk factor for late-onset AD, the e4 allele of the apolipoprotein E gene (APOE4), increases AD risk more strongly in women than men. Sex is also an important regulator of glial cells, which not only are the primary neural source of ApoE protein but also are strongly implicated in AD pathogenesis. Interestingly, carriers of APOE4 exhibit increased activation of microglial cells, leading to the widely held position that APOE4 increases AD risk at least in part by its regulation of microglial activation states. Interest in the relationships among APOE4, microglia, and AD have strengthened considerably with new findings that connect TREM2 with all three. A recently identified mutation in TREM2 yields a genetic risk factor for AD than is approximately as robust as APOE4 in its linkage to AD. In brain, TREM2 is expressed almost exclusively in microglia. Recent advances have identified an ApoE-TREM2 signaling pathway that regulates microglial functions in manners that are highly relevant to AD. What is completely unknown is how sex affects interactions among APOE4, TREM2, and microglia that are implicated in AD pathogenesis.

Our studies are investigating three hypotheses:

(i) TREM2 regulation of microglia is significantly affected by sex,
(ii) TREM2 regulation of microglia is significantly affected by APOE genotype, and
(iii) interactions between TREM2 and APOE differ by sex.