New Links in the Risk for Alzheimer’s Disease

Orlando—The search for an effective treatment for Alzheimer’s disease (AD) has been elusive. While beta-amyloid and phosphorylated tau protein have been research targets, the positive results of early trials have not been validated. Research efforts are now being focused on the identification of risk factors and preventative treatments.

Links have been found between cardiovascular, hypertension, and metabolic abnormalities, including diabetes, in the development of AD. Also, research into hormonal factors has led to early clinical trials with estrogen as a potential preventative treatment. Faculty from the University of Southern California School of Pharmacy and Davis School of Gerontology discussed emerging concepts in the risk for AD during a session at the ASCP meeting. Presenters included Tara Rose, BS, PhD, adjunct clinical associate professor of psychology, and Bradley Williams, PharmD, professor of clinical pharmacy and clinical gerontology.

Studies on cardiovascular risk and cognition have found carotid atherosclerosis and intima-media thickening are associated with cognitive decline; increased arterial stiffness is a predictor for cognitive decline; and increased pulse pressure is associated with reduced cognition.

The presenters highlighted a study published in 2012 in Neurobiology of Aging that examined coronary risk factors and cerebral amyloid deposition. The study included 43 patients with normal cognition or mild cognitive impairment (MCI). Vascular risk was quantified using the Framingham Coronary Risk Profile (FCRP) score. The Pittsburgh compound B positron emission tomography was used to measure amyloid deposition. The results showed that high FCRP scores were correlated with amyloid deposition. ApoE genotype was also independently associated with amyloid deposition.

In a separate study, researchers examined vascular risk factors and cognitive function. The study included 74 older patients with normal cognition who underwent at least 2 neuropsychological evaluations and 2 magnetic resonance imaging examinations over an average follow-up of 6.9 years. The findings, published in Journal of the American Geriatric Society in 2012, indicated that a history of coronary artery disease was associated with declines in global cognition, verbal memory, and executive function. These changes were independent of white matter hyperintensities, silent brain infarcts, hippocampus, and cortical gray matter.

Drs. Rose and Williams also explored the link between hypertension and cognitive function, citing a 2013 study published in Journal of the American Geriatric Society, which investigated the long-term prospective associations of hypertensive status in midlife and cognitive impairment 20 years later. The researchers found that lower cognition was associated with low and high diastolic pressure, low and high mean arterial pressure, and higher evening diastolic pressure on ambulatory monitoring.

The presenters discussed the risk of diabetes on dementia, referencing a meta-analysis of longitudinal studies published in 2012 in Internal Medicine Journal, which examined the onset of dementia, including AD, vascular dementia and any dementia, and MCI. The results demonstrated that diabetes patients had a higher risk of AD (relative risk [RR], 1.54), vascular dementia (RR, 2.48), any dementia (RR, 1.54), and MCI (RR, 1.02).

Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function. In the body, estrogen protects against adiposity, insulin resistance, and type 2 diabetes and regulates energy intake and expenditure. Drs. Rose and Williams said the potential role of estrogen in the management of AD has been demonstrated in animal studies. These studies have shown increased upregulation of glucose and glycolysis, along with increased mitochondrial respiratory rate in the brain, which may preserve function.

They also discussed hormone therapy for reducing the risk of AD, noting that early studies have demonstrated mixed results. Furthermore, the effect of targeted hormonal therapy may depend on the dose, route of administration, and timing of dosing.

The presenters concluded the session with a discussion on therapeutic strategies to mitigate the effects of risk factors. “Prevention or delay of onset may be more achievable at the present time than a cure or slowing of progression [of AD],” said Drs. Rose and Williams.

They recommended treatment of hypertension in early to midlife. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have demonstrated early evidence of benefit. “Regardless of the chosen treatment, blood pressure [(BP)] control is critical,” they said. Management of metabolic syndrome and diabetes has multiple benefits, such as weight loss, reduced obesity, BP control, and management of hyperlipidemia. Hormone therapy may be the most useful tool to manage metabolic risks, for now, according to the presenters.—Eileen Koutnik-Fotopoulos