Apathy and Negative Symptoms in Alzheimer's Disease: Investigation of the Proline*COMT Interaction for Symptom Targeting to Positively Impact Quality of Life

Patients with Alzheimer's disease (AD) and those who have had a traumatic brain injury (TBI) very often become socially withdrawn and emotionally unresponsive. They have loss of speech and movement, and can lack motivation; symptoms which are collectively known as 'negative symptoms.' In fact, studies have shown that half of AD and TBI patients have negative symptoms, and these symptoms often start to occur during the very early stages of disease or shortly after brain injury. These symptoms can severely affect the quality of life for these patients, primarily because they can cause serious damage to relationships with family and friends. However, it is not just the quality of life of the patient that can be affected by these symptoms: Many caregivers and family members report substantial burden and distress when caring for a patient who has negative symptoms. There are currently no approved treatments that can improve these symptoms. Of particular relevance to the goals of the Peer-Reviewed Alzheimer's Research Program (PRARP), our preliminary studies have identified a biological pathway that could be targeted to treat negative symptoms using medications that already exist. This biological pathway involves an amino acid called 'proline,' which can function in the brain to modify the levels and activity of neurotransmitters, together with the catechol-O-methyltransferase (COMT) gene, which is involved in the break-down of neurotransmitters. In our recent study we found that levels of blood proline (which indicates levels in the brain) are closely related to the severity of negative symptoms displayed by patients with psychiatric illnesses. Importantly, we found that the severity of these symptoms were increased in patients with high proline if they had one or two copies of a common DNA variant in the COMT gene called the 'Met variant.' However, in patients who did not have this DNA variant, who instead had two copies of the alternate 'Val variant,' negative symptom severity was low when they had high proline. We have also shown that changes in proline level are closely related to changes in negative symptom severity, and we consider this provides support for our hypothesis that having high or low proline can cause, or at least modify, the severity of negative symptoms based upon which version of the COMT gene you have (Met or Val).

In our earlier studies we found that the relationship between proline and COMT was the same in patients with two different psychiatric illnesses; schizophrenia and bipolar disorder. We therefore hypothesize that this relationship may be generalizable to other diseases where negative symptoms are present, such as AD. In this proposed study we will test this hypothesis. For this first study in this area, we will focus on patients with AD, because over half of these patients have severe negative symptoms and importantly, studies have been published showing abnormal proline levels in both the blood and cerebrospinal fluid (which bathes the brain) of AD patients. Future studies will then investigate patients with TBI.

Study Aims: We will investigate 112 female AD patients, all of whom have negative symptoms. We will measure symptom severity and we will test whether those with high proline and the COMT Met variant have more severe negative symptoms than those with high proline and the COMT Val/Val variant. We will focus on females because, of the over 5 million AD sufferers in the US, nearly two-thirds are women. Also, from study of one gender we seek to limit possible gender differences, providing focus to this first AD study. If we find a similar relationship between proline and COMT in patients with AD, as we did with other brain diseases, this study may lead to improved treatments for negative symptoms of AD, because there are medications that are known to change proline levels, including valproate (which boosts proline levels) and vitamin D (which likely decreases proline). In addition, obtaining personalized genetic (COMT)/biochemical (proline) biomarker information may help doctors maximize treatment benefits while at the same time minimizing potential risks, such as avoiding prescribing medications that may boost proline level in patients with the Met variant who have negative symptoms.

Successfully treating negative symptoms in AD (and in the future TBI) may help patients achieve a higher quality of life, while simultaneously reducing caregiver burden. For these reasons this proposal is suited to both the Quality of Life (QUAL) and Caregiver Burden Overarching Challenges. The potential for proline/COMT to act as a biomarker for treatment choice, coupled with the potential for new treatment approaches for negative symptoms, makes this proposal responsive to both the Biomarker and QUAL Focus Areas. In summary, alleviating negative symptoms of AD and TBI via proline-regulating medications may increase the QUAL of affected individuals and reduce the burden on their caregivers and other family members, thus potentially impacting thousands of Americans from civilian, military, and veteran communities, and for these reasons this study and its potential directions are particularly suited to PRARP's mission.