In order to solve the problem of long-term (

>

9 months) efficacy in the treatment of Alzheimer's disease (AD) by conventional therapy (CT)

a staged and multiply-targeted sequential therapy based on the evolvement of patterns (STEP) was developed. Its main innovations include: (1) the time order of evolution of patterns defined by Chinese medicine (CM) in AD was found

that is

"the orderly pattern evolution starting from Shen (Kidney) deficiency

progressing to phlegm

stasis and fire

and worsening to severe toxin as well as functional collapse"; (2) the cascade hypothesis of Shen deficiency in AD and its sequential therapy based on Shen-reinforcing was proposed

that is

"reinforcing Shen in the early stage and throughout the whole process

resolving phlegm

activating blood and purging fire in the middle stage

detoxifying and replenishing vitality to stop the collapse in the advanced stage"

and through meta-analysis

clinical drug use was optimized

thus the leap from "inferential selection" to "evidence-based selection" was realized; (3) the STEP regimen combined with CT maintained cognitive and behavioral stability in AD patients for at least 12 months

with cognitive enhancement and behavioral synergy after 9 months

and cognitive benefit was superior to CT at 9

12

15

18

21

and 24 months

respectively. The 2-year cognitive improvement rate was increased by 25.64% (

P

=0.020) and the cognitive deterioration rate was decreased by 48.71% (

P

=0.000). Among them

the cognitive and functional benefits of Shen-reinforcing therapy for very early AD (350 cases) for 1 year were better than the placebo (

P

<

0.001)

and the dementia conversion rate was reduced by 8.85% (

P

=0.002). The behavioral symptomatic relief of patients with vascular dementia received fire-purging therapy (540 cases) was superior to those received CT (

P

=0.016). These data suggested that the STEP regimen has synergistic effects on CTs at least in terms of cognitive benefit

and the earlier the use

the greater the benefit will have. Therefore

the STEP regimen should be considered as one of the clinical options

particularly for the dearth of effective pharmaceutical or immunological interventions that are currently available for AD.