Screening and Assessment for Alzheimer’s Disease in the Days of Biological Biomarkers

The 1980s proved to be a pivotal decade for Alzheimer’s disease (AD) research. AD was finally recognized as being an illness separate from simply the aging process and acknowledged as a major public health problem. This distinction was due, at least in part, to an editorial by Katzman, which was published a few years prior, in 1976 [1]. The Alzheimer’s Association, which has become the leading advocate for research into AD and a source of support and information to AD patients and their families was founded in 1980. At the same time, funding for Alzheimer Disease Research began to increase, and the first NIA funded Alzheimer Disease Centers were established in 1984. These Centers were the first of six NIH Centers of excellence to be mandated by statute.

It was in this atmosphere, as described in the article by Fillenbaum and Mohs [2], that the research community and the research centers quickly realized the necessity of a standardized clinical evaluation [2]. This led to the development of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) [2]. The CERAD assessment battery, particularly the CERAD neuropsychological assessment battery (CERAD NAB), was quickly accepted by the research community and applied to a variety of research projects.

Similar assessment tools have evolved in other countries. In Britain, Martin Roth was, for many years, a leading researcher in AD. In 1968 he had co-authored a paper that increased awareness of disorders associated with aging [3], and in the 1980s, together with his colleagues, he developed the Cambridge Mental Disorders of the Elderly Examination (CAMDEX) [4]. This assessment battery was quickly adopted by the research community in Britain and elsewhere, both for epidemiological and clinically based studies [5].

We were pleased to use a suitably translated version of the CERAD NAB in our ongoing clinical assessment portion of the Indianapolis-Ibadan study [6]. For the screening portion, beginning with our pilot study with Cree [7], we designed the Community Screening Instrument for Dementia (CSI ‘D’), which consisted not only of neuropsychological evaluations but also clinical and historical data [8].

It is remarkable how well these instruments have stood the test of time, and it is a tribute, I believe, not only to their reliability and validity but also to their usability. The CERAD story is well described in the Fillenbaum and Mohs paper [2], with the CERAD NAB and later the CERAD PLUS adding assessment of executive function and a broader version for verbal functioning [2]. The CAMDEX [9] versions are still being used, including the CAMDEX-DS, for assessing patients with Down syndrome [10, 11] and an extension of the CAMDEX that assesses subcortical, executive and frontal functions [12]. Our CSI ‘D’ is still being used in international studies with component parts being included in the very successful 10/66 studies [13].

The question raised now is, what is the relevance of these assessment batteries in the days of biological biomarkers for AD?

Fillenbaum and Mohs have provided some answers [2]. The association of the biomarkers with clinical dementia is still unclear, and the need for symptomatic assessment in clinical trials is still necessary. As cognitive function plays a primary role in the diagnosis and progression of AD, assessment of cognitive function remains paramount. Fortunately, there has been considerable advances both in measurement of cognitive function and in assessment techniques. The development of the NIA Toolbox, which has attention, episodic memory, working memory, language, executive function, and processing speed in its cognitive component, in addition to its emotion, sensation and motor components, is one example [14 –16].

Also, AD biomarkers such as amyloid PET, amyloid tau, analyses of cerebrospinal fluid and recent p-tau217 and other AD biomarkers do not fully explain the many co-morbidities and pathologies seen on neuropathological examination of the brain and may differ in diverse ethnic and cultural groups. Ethnic minority groups, particularly Black, African American, and American Indiana/Native American populations, also have increased rates of clinical risk factors as well as possible differing genetic risk factors from White populations and higher rates of AD, yet their participation in AD research studies have been low [17 –20]. It is essential that every step be taken to assure their inclusion in these biomarker studies [21].

One goal is that eventually plasma biomarkers may be used to diagnose pre-clinical AD. However, it is now recognized that the earliest prodromal symptoms of AD may not be cognitive decline but emotional or behavioral symptoms, such as depression, anxiety, and apathy [22 –30]. It has also been suggested that midlife depression may be a risk factor for later onset AD [22]. Thus, while it makes sense to use neuropsychological data to identify and monitor clinical AD, where cognitive decline is an essential diagnostic criterion and when emotional symptoms may or may not be present, the case is not the same for research involving the early biomarkers when the prodromal symptoms may be either cognitive or emotional/behavioral. It is also likely that biological testing for AD may not become routine for all patients but will depend on the presenting symptoms of the patient. Therefore, it is important that research trials utilizing plasma biological markers also measure emotional and behavioral symptoms in addition to cognition.

In a previous NIA funded report for the Cognitive and Emotional Health Project [31], in part because cognition and emotion were inextricably linked, one recommendation was, “The committee proposes that an attempt be made to construct a questionnaire for assessment of cognitive and emotional health that could be used in current large cohort studies and be recommended for use in future studies. The proposed questionnaire needs to be multidimensional but as brief as possible making it useful for large cohort studies without making it too much of a burden for participants of the study.” [31] This may be the time to apply this recommendation to the forthcoming biomarker studies. Creating this questionnaire with brevity, however, may be difficult.

Now, with the possible advent of accessible biomarkers, sophisticated clinical assessments and the potential for disease modifying new treatments, exciting days are back for our understanding and treatment of AD.