We aim to better understand the links between type 2 diabetes (T2D) and Alzheimer’s disease (AD).
Although the literature supports their association, the underlying mechanisms are not known. A number of
obesity-associated comorbidities contribute to cerebrovascular abnormalities in T2D; among them: impaired
glucose control, low grade systemic inflammation, hypertension, dyslipidemia, and obstructive sleep apnea.
These comorbidities provide possible mechanistic links between T2D and dementia. Importantly, this group of
comorbidities (here referred to as “modifiable vascular factors”) improve with weight loss. In addition to the
fact that T2D is related to a doubling of all-cause dementia, individuals with T2D and those with prodromal AD,
share a cluster of CNS abnormalities (here referred to as “CNS impairments”): memory deficits, hippocampal
atrophy, reductions in cerebral glucose uptake in AD-vulnerable regions, and decreased cerebral blood flow.
This overlap in CNS abnormalities supports a potential common pathway for the brain abnormalities observed
in T2D and prodromal AD. We propose that large weight loss, which results in improvements of these
modifiable vascular factors, will lead to recovery of the above mentioned central nervous system (CNS)
impairments associated with T2D. We will conduct a longitudinal study comparing 100 obese individuals with
T2D undergoing bariatric surgery to an equivalent group of 40 obese individuals also with T2D who will not
have surgery (and likely not lose weight or improve in the modifiable vascular factors). The anticipated large
changes in weight after bariatric surgery present a unique opportunity to investigate how obesity is causally
related to CNS impairments. Subjects, 35-55 years old, with baseline BMI of 30-50 kg/m2 and 50% female, will
be studied twice, immediately pre-surgery (baseline) and one year post-surgery, and an equal interval for the
non-surgical obese T2D group. CNS recovery from injury or stroke shows large individual variability, thus we
will determine how sex, education, and fitness moderate CNS recovery of the impairments associated with
T2D resulting from large weight loss. We will also ascertain whether glycemic control and other modifiable
vascular factors and their change over one year mediate the relationships between weight loss and recovery of
the CNS impairments during that period. Both T2D and dementia are significant public health problems. This
study will provide evidence to justify prevention strategies targeting modifiable vascular risk factors that likely
contribute to the increased risk of dementia among individuals with T2D. By targeting modifiable vascular
factors at a young age, prior to potential irreversible brain deterioration, we will show the importance of this
approach among young adults, when interventions may be most effective. We will utilize reliable and validated
measures so as to ensure reproducibility. The study has a strong scientific premise and has been adequately
powered. Success is assured by the access to participants, an excellent environment, and the experience and
productivity of the investigators.