Clearance of amyloid beta

A method of reducing the fail in Aβ42 in CSF of patients which comprises administering thereto a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-el][2] benzazepin-6-ol of the formula:

• wherein R1 is a monoalkyl carbamate group having from 1-10 carbon atoms in the alkyl group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, or an alkanoyloxy group or 2 to 10 carbon atoms, and R3 is hydrogen or alkyl of 1 to 10 carbon atoms or a pharmaceutically acceptable salt thereof to a patient who has been assessed by one or more standard tests:
• MMSE, ADAS-cog, Logical Memory Delayed Paragraph Recall, WAIS-R Digit Symbol Substitution, CDR-global, CIR-SB, NTB, logical memory IIA (delayed) and IA (immediate), category fluency, delayed and immediate word-list recall, progressive matrices, ELSMEM, CogState, trailmaking, executive function, neuromotor speed, ADCS-ADL, DAD, and others, or a composite test composed of elements of these or other tests, to have impaired cognition or function, but not to be displaying dementia, and not having a condition not associated with Alzheimer pathology to which the impaired cognition or function can be solely attributed so as to delay deterioration of cognition and/or function.

A method of reducing the fall in Aβ42 in CSF of patients not exhibiting signs of dementia comprising administering a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef] [2] benzazepin-6-ol of the formula:

• wherein R1 is a monoalkyl having from 1-10 carbon atoms in the alky group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, or an alkanoyloxy group of 2 to 10 carbon atoms;
• and R3 is hydrogen or alkyl of 1 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof to a patient whose CSF Aβ42 is decreasing.

A method of treating patient not exhibiting signs of dementia which comprises administering a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS )-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1] benzofuro[3a,3,2-ef] [2] benzazepin-6-ol of the formula:

• wherein R1 is a monoalkyl carbamate having from 1-10 carbon atoms in the alkyl group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, or an alkanoyloxy group of 2 to 10 carbon atoms and R3 is hydrogen or alkyl of 1 to 10 carbon atoms;
• or a pharmaceutically acceptable salt thereof to a patient in need thereof in combination with a nicotinic agonist in order to inhibit plaque deposition or aid in removal of plaques of Aβ, prevent the decrease or cause an increase in Aβ42 in CSF, delay progression to Alzheimer's disease dementia, or reduce the loss of cognition and/or activities of daily living.

A method of treating an individual who has been determined to have the ApoE4 isoform of Apolipoprotein E which comprises administering thereto a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol of the formula:

• wherein R1 is a monoalkyl carbamate having from 1-10 carbon atoms in the alkyl group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, or an alkanoyloxy group of 2 to 10 carbon atoms, and R3 is hydrogen or alkyl of 1 to 10 carbon atoms;
• or a pharmaceutically acceptable salt thereof to a patient who has been determined to have the ApoE4 isoform of Apolipoprotein E but who is not exhibiting signs of dementia in an amount sufficient to inhibit plaque deposition or aid in removal of plaques of Aβ, or to reduce the fall in CSF Aβ42, or prevent progression of cognitive and/or functional decline, or prevent progression to Alzheimer's dementia.

A method of reducing the fall in Aβ42 in CSF of patients exhibiting a decreased Aβ42 level in CSF or one which is falling at >1%/year, or more than 10% from baseline, or falling on two successive postbaseline samples at least three months apart, but not exhibiting signs of dementia which comprises administering thereto a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef] [2] benzazepin-6-ol of the formula:

• wherein R1 is a monoalkyl carbamate having from 1-10 carbon atoms in the alkyl group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, or an alkanoyloxy group of 2 to 10 carbon atoms and R3 is hydrogen or alkyl of 1 to 10 carbon atoms or a pharmaceutically acceptable salt thereof to a patient who has been determined to carry a fully-penetrant mutation which causes Alzheimer's dementia.

A method to improve performance or slow decline greater than expected for age in a patient not exhibiting signs of dementia which comprises administering thereto a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS]-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1] benzofuro[3a,3,2-ef] [2] benzazepin-6-ol of the formula:

• wherein R1 is a monoalkyl carbamate having from 1-10 carbon atoms in the alkyl group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, or an alkanoyloxy group of 2 to 10 carbon atoms and R3 is hydrogen or alkyl of 1 to 10 carbon atoms or a pharmaceutically acceptable salt thereof.

A method to delay the onset of dementia in patients having a CSF Aβ to tau ratio below the discrimination line determined by Aβ42=240+1.18 ×tau, or a ratio of CSF Aβ1-42 to tau less than 6.16, but not exhibiting signs of dementia which comprises administering thereto a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1] benzofuro[3a,3,2-ef] [2] benzazepin-6-6-ol of the formula:

• wherein R1 is a monoalkyl carbamate having from 1-10 carbon atoms in the alkyl group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, or an alkanoyloxy group of 2 to 10 carbon atoms, and R3 is hydrogen or alkyl of 1 to 10 carbon atoms or a pharmaceutically acceptable salt thereof.