To　date,　earlier　diagnosis　of　Alzheimer＇s　disease　(AD)　is　still　challenging.　Recent　studies　revealed　the　elevated　expression　of　connective　tissue　growth　factor　(CTGF)　in　AD　brain　is　an　upstream　regulator　of　amyloid-beta　(A　beta)　plaque,　thus　CTGF　could　be　an　earlier　diagnostic　biomarker　of　AD　than　A　beta　plaque.　Herein,　we　develop　a　peptide-coated　gold　nanocluster　that　specifically　targets　CTGF　with　high　affinity　(KD　similar　to　21.9　nM).　The　probe　can　well　penetrate　the　blood-brain-barrier　(BBB)　of　APP/PS1　transgenic　mice　at　early-stage　(earlier　than　3-month-old)　in　vivo,　allowing　non-invasive　NIR-II　imaging　of　CTGF　when　there　is　no　appearance　of　A　beta　plaque　deposition.　Notably,　this　probe　can　also　be　applied　to　measuring　CTGF　on　postmortem　brain　sections　by　multimodal　analysis,　including　fluorescence　imaging,　peroxidase-like　chromogenic　imaging,　and　ICP-MS　quantitation,　which　enables　distinguishment　between　the　brains　of　AD　patients　and　healthy　people.　This　probe　possesses　great　potential　for　precise　diagnosis　of　earlier　AD　before　A　beta　plaque　formation.