High-resolution scans of immunohistochemical (IHC) stains of Alzheimer's disease (AD) brain slices and radioligand autoradiography both provide information about the distribution of Aβ plaques and Tau, the two common proteinopathies in AD. Accurate assessment of the amount and regional location of Aβ plaques and Tau is essential to understand the progression of AD pathology. Our goal was to develop a quantitative method for the analysis of IHC-autoradiography images. Postmortem anterior cingulate (AC) and corpus callosum (CC) from AD and control (CN) subjects were IHC stained with anti-Aβ for Aβ plaques and autoradiography with [¹⁸F]flotaza and [¹²⁵I]IBETA for Aβ plaques. For Tau, [¹²⁴I]IPPI, a new radiotracer, was synthesized and evaluated in the AD brain. For Tau imaging, brain slices were IHC stained with anti-Tau and autoradiography using [¹²⁵I]IPPI and [¹²⁴I]IPPI. Annotations for Aβ plaques and Tau using QuPath for training and pixel classifiers were generated to measure the percent of the area of Aβ plaques and Tau in each slice. The binding of [¹²⁴I]IPPI was observed in all AD brains with an AC/CC ratio > 10. Selectivity to Tau was shown by blocking [¹²⁴I]IPPI with MK-6240. Percent positivity for Aβ plaques was 4-15%, and for Tau, it was 1.3 to 35%. All IHC Aβ plaque-positive subjects showed [¹⁸F]flotaza and [¹²⁵I]IBETA binding with a positive linear correlation (r² > 0.45). Tau-positive subjects showed [^124/125I]IPPI binding with a stronger positive linear correlation (r² > 0.80). This quantitative IHC-autoradiography approach provides an accurate measurement of Aβ plaques and Tau within and across subjects.

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