• Behavioral & Mood measure: Profile of Mood States (POMS) [ Time Frame: Baseline, 3 and 6 months ] [ Designated as safety issue: No ]
• Cognitive changes measured by Neuropsychological tests: ADAS-Cog (MCI version), Route Test, Paragraph recall [ Time Frame: Baseline, 3 and 6 months ] [ Designated as safety issue: No ]
• Cerebrospinal Fluid (CSF) [ Time Frame: Baseline and 6 months ] [ Designated as safety issue: No ]
• APOE genotyping [ Time Frame: Baseline ] [ Designated as safety issue: No ]

• Behavioral & Mood measure: Profile of Mood States (POMS) [ Time Frame: Baseline, 3 and 6 months ]
• Cognitive changes measured by Neuropsychological tests: ADAS-Cog (MCI version), Route Test, Paragraph recall [ Time Frame: Baseline, 3 and 6 months ]
• Cerebrospinal Fluid (CSF) [ Time Frame: Baseline and 6 months ]
• APOE genotyping [ Time Frame: Baseline ]

The purpose of this study is to examine the effects of testosterone (T) replacement on changes in thinking and memory, as well as mood in older men with mild cognitive impairment (MCI) and low T levels. The study will also examine whether taking testosterone has effects on biological markers related to Alzheimer's disease.

Natural age related declines in testosterone (T) are associated with decreases in cognitive abilities independent of health status. Low T levels over time are associated with increased risk for developing Alzheimer's disease (AD). These findings suggest that men with low T levels are most at risk for age-related cognitive decline and AD and therefore most likely to benefit from T supplementation to prevent the development of AD or age-associated cognitive decline. The current study will assess cognition, mood, and cerebral spinal fluid (CSF) biomarker response to T supplementation in older men with mild cognitive impairment (MCI) and low T levels.

Participants will be randomized to either receive T treatment or a placebo for six months. Participants will come in for about five visits within the span of six months where they will complete cognitive & memory tests, fill out mood questionnaires, and have their blood drawn to monitor the medication level. A sample of blood will also be taken at one visit to test for apolipoprotein E (APOE), which is a genetic risk factor associated with AD. Participants will have the option to get a spinal tap in order to measure biological markers associated with Alzheimer's disease including beta-amyloid 1-40, 42, total-tau, and phosphorylated-tau-181-231. This will require an additional two visits.

• Mild Cognitive Impairment
• Alzheimer's Disease

• Drug: testosterone gel
• Drug: placebo gel

• Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, Raskind MA, Brodkin K, Bremner W, Petrova A, LaTendresse S, Craft S. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology. 2001 Jul 10;57(1):80-8.
• Cherrier MM, Matsumoto AM, Amory JK, Ahmed S, Bremner W, Peskind ER, Raskind MA, Johnson M, Craft S. The role of aromatization in testosterone supplementation: effects on cognition in older men. Neurology. 2005 Jan 25;64(2):290-6.
• Cherrier MM, Matsumoto AM, Amory JK, Asthana S, Bremner W, Peskind ER, Raskind MA, Craft S. Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology. 2005 Jun 28;64(12):2063-8.
• Cherrier MM, Matsumoto AM, Amory JK, Johnson M, Craft S, Peskind ER, Raskind MA. Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men. Psychoneuroendocrinology. 2007 Jan;32(1):72-9. Epub 2006 Dec 4.
• Lu PH, Masterman DA, Mulnard R, Cotman C, Miller B, Yaffe K, Reback E, Porter V, Swerdloff R, Cummings JL. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol. 2006 Feb;63(2):177-85. Epub 2005 Dec 12.

Inclusion Criteria:

• Male 60-90 years of age
• Diagnosis of mild cognitive impairment (MCI)
• Low testosterone level
• Primary language is English
• Availability of an informant who knows the participant well enough to answer questions
• Stable medications for the previous 3 months
• Normal complete blood count (CBC), calcium, albumin, TSH, and no clinically significant blood chemistry
• American Urological Association (AUA) symptom score less than or equal to 19
• Body Mass Index (BMI) less than 33 and stable weight in the previous year

Exclusion Criteria:

• Prior history of prostate cancer or prostate specific antigen level greater than 4.0ng/ml
• Peripheral or vascular disease
• Significant history of alcohol abuse, current alcohol abuse (more than 2 drinks per day), or other substance abuse
• History of severe head injury (with loss of consciousness greater than 30 minutes)
• Significant neurological illness, such as Parkinson's disease, seizure disorder, multiple sclerosis, major stoke
• Smokes cigarettes
• Major psychiatric illness, such as schizophrenia or bipolar disorder

Prohibited Medications:

• Anti-convulsants
• Anti-psychotics
• Sedating antihistamines
• Sedative/hypnotics
• Benzodiazepines
• Hormone or testosterone regimens
• GNRH antagonists
• Flutamide
• Anti-depressants and/or anti-cholinesterase inhibitors, but acceptable if on stable dose for 3 months or more