The incorporation of target engagement, efficacy, and imaging abnormalities biomarkers on preclinical (animal) drug development brings the promise of accelerating drug development. In this chapter, we will highlight innovative methodological considerations that will bring greater predictive power relative to the traditional approaches in the preclinical stage of drug discovery. First, we discuss various animal models used in Alzheimer’s disease research and important aspects to consider when choosing the appropriate model to test a novel therapeutic intervention. Second, compared to the traditional histological methods, utilizing in vivo biomarkers in preclinical assessment allows quantifying disease pathophysiology with complex longitudinal designs. We discuss the feasibility and implications of longitudinal study designs and how the same in vivo biomarkers used in human clinical trials can be implemented to evaluate the preclinical development stages. Lastly, we discuss why the incorporation of methods from human clinical trials can advance the preclinical phases of drug discovery.

A 65-year-old accountant presented to the consultation to investigate whether her memory lapses are the first manifestations of Fahr’s disease. She noticed, during the last few years, a progressive difficulty in accomplishing her tasks at work. She felt tired and described that it takes her more time to prepare her reports as compared to a few years ago. She needs to read her drafts several times in order to ensure her work is complete and accurate. She also described more dependence on her personal notes to remember her tasks such as lists for shopping. During meetings and conversations at work, she described difficulties recalling people’s names. She has started to search for words during conversations. Although inconvenient, the impact of these difficulties on her work remains minimal, and she continues to take good care of her home affairs. Her husband denies that the patient is underperforming at home. She described no difficulties completing her domestic, financial, and personal obligations.

A 62-year-old male (Patient 1) was admitted to the Capital Medical University Hospital, in Beijing, China, because of a 3-month history of progressive cognitive impairment and abnormal behaviors including performing motor gestures and talking to himself incoherently. During the first evaluation, it was reported that the patient had insomnia as an early clinical manifestation accompanied by intense dreams and sleep talking. During the 14 days of hospitalization, the patient showed intractable insomnia, progressive cognitive deterioration, mental confusion, visual and auditory hallucinations, and paranoia. Twelve months after the onset of the symptoms, the patient returned to the hospital awake but unresponsive and died due to breathing difficulties.

An 80-year-old man came to the consultation with problems in writing a thesis.

A 75-year-old, right-handed man accompanied by his wife presented at initial consultation, with a history of mild difficulties with short-term recall for the past 2 years. Although he wrote down the time and place of upcoming appointments accurately, he repeatedly sought reassurance from his wife about them. He kept rechecking where things had been deposited. There was some hesitation for words during conversations.

Decline in memory function.

Mrs. M is a 79-year-old active and independent lady who lives with her 88-year-old husband. She has been serving as his caregiver since his AD dementia diagnosis. Both cohabit with each other in the same house for more than 30 years. She has been responsible for maintaining their home, preparing meals, and has taken care of their financial affairs for many years. Mrs. M was invited to participate in a 3-year longitudinal study, as a cognitively healthy person, involving magnetic resonance imaging (MRI) and positron emission tomography (PET) scans for amyloid plaques, neurofibrillary tangles, and glucose metabolism.

A young 41-year-old man with memory problems and walking difficulties.

A 55-year-old priest who retired due to significant cognitive decline.