A positive first-degree family history of Alzheimer’s disease increases the risk to develop the disease (van Duijn et al. 1991
; Fratiglioni et al. 1993
; Cupples et al. 2004
). Family history and APOE-4 genetic risks highly co-occur (Zintl et al. 2009
) and it remains controversial whether both risk factors contribute additively to Alzheimer’s disease development, whether they interact and overlap. This points to some intrinsic limitations of the family history approach. The pattern of risk variables embodied in family history risk is presumably heterogeneous across different subjects and study populations, and the interaction potential of these variables with other given factors, such as the APOE-4 allele, may vary on the individual level. Relatives with dementias other than Alzheimer’s disease could be misclassified based on clinical criteria, and healthy relatives could develop Alzheimer’s disease in the future. Moreover, in the presence of both risk factors, it cannot be determined clinically whether the familial clustering of the disease is mainly driven by the APOE-4 allele. However, it has been demonstrated across various neurobiological and clinical studies that family history associated effects are often dissociable from APOE-4 related effects.
Data from fMRI studies suggest that a different family history status may even influence the direction of neural activity changes during cognitive tasks. The studies by Johnson and colleagues (2006)
and Xu and colleagues (2009)
are great examples for how interesting fMRI findings could have been overlooked if one would chose not to model the individual effects of APOE-4 and family history risks. Studies of APOE-4 associated effects as they relate to fMRI findings have yielded variable results, especially when compared with structural MRI findings. Such variability likely reflects several challenges and limitations. The biological basis of BOLD signal dynamics may reflect the interplay of neural activity, metabolism, blood volume, blood flow and subsequent oxygenation changes (Bandettini and Ungerleider 2001
). Logothetis and colleagues (2001)
showed that a spatially localized increase in the BOLD signal directly and monotonically reflects an increase in neural activity, specifically local field potential rather than the neuronal spiking activity. However, it is possible that the BOLD signal and local field potential dissociate. Caution is necessary when interpreting BOLD data, and making direct inferences about underlying neural activity (Ekstrom 2010
). BOLD signal increase during cognitive tasks in people at risk for Alzheimer’s disease may be interpreted as ‘compensatory’, reflecting the recruitment of additional neural resources to aid task performance. Decreased BOLD signal could be interpreted as an indication of regional neuronal loss in the same risk population, however, BOLD signal decrease could also reflect better brain efficiency. Correlations with cognitive performance scores from tasks performed during fMRI scanning can help guide investigators to meaningful interpretations of the BOLD signal. It is obvious that fMRI itself cannot be used to determine whether, and under which circumstances one of these hypotheses is more likely to be true than others. Many questions about Alzheimer’s disease risk factors and their association with BOLD signal changes and directionality may remain unanswered. However, there is evidence that APOE-4 and family history risk can influence the BOLD response. In general, age, APOE-4, and family history risk need consideration when interpreting neuronal function in the context of BOLD signal direction.
Structural MRI investigations show clear evidence of independent and/or additive effects of family history and APOE-4 risks on regional cortical thickness patterns (Donix et al. 2010a
) or white matter integrity (Bendlin et al. 2010
). This might be helpful to more precisely determine the unique APOE-4 associated effects on brain morphology. Neurocognitive profiles suggest family history effects in various cognitive domains, whereas APOE-4 effects may preferentially occur in memory tasks (Donix et al. 2011
). This would be in line with the hypothesis that the presumable diversity of risk factors embodied in family history risk may involve factors less closely related to Alzheimer’s disease pathology.
An interesting finding from structural MRI, PET and CSF data is the possible significance of having a maternal rather than paternal family history of Alzheimer’s disease (Honea et al. 2010
; Mosconi et al. 2007
; Mosconi et al. 2010a
). It indicates that modeling family history risk does not only allow to better isolate and describe APOE-4 related phenomena; it may also enhance our understanding of sporadic Alzheimer’s disease genetic transmission. Mosconi and colleagues (2007)
suggest the possibility of a mitochondrial DNA inheritance pattern, which would be in line with the mechanisms contributing to reduced brain (glucose) metabolism and changes in the oxidative microenvironment (Mosconi et al. 2010a
; Lin and Beal 2006
In summary, the reviewed data indicate that APOE-4 carrier status modulates brain structure and function. The underlying molecular mechanisms often remain unknown because of the limited knowledge about the physiological functions of APOE proteins, which play an important role in neural lipid metabolism. In contrast to the e2 and e3 isoforms, the APOE-4 allele has poorer functionality, is conformationally unstable, increases amyloid production and tau phosphorylation and may even have direct neurotoxic effects (Mahley et al. 2006
). The APOE-4 allele is associated with reduced neural repair and plasticity (Teter 2004
) and may be a general risk factor for neurodegenerative diseases (Blazquez et al. 2006
; van Duijn et al. 1994
; Chapman et al. 2001
). The mechanisms through which a family history of Alzheimer’s disease becomes a risk factor may be even more complex. On the one hand, family history risk may reflect the presence of genetic risk factors ranging from established susceptibility genes with only partially known roles (e.g., APOE) to yet unknown genetic variables. On the other hand, family history risk could also reflect non-genetic risks, such as low socioeconomic status (Borenstein et al. 2006
) that may be passed on through generations, as well as shared environmental risks that family members may be exposed to (e.g., mold in family dwellings, exposure to toxins, etc.). Future research might further detail familial risks (e.g., first degree vs. second degree relatives, potential influence of environmental factors) and the underlying risk mechanisms.
For researchers it may be important to recognize family history effects in studies aimed at investigating APOE-4 associated changes irrespective of the research modality. Until we can better separate the single variables that likely contribute to family history risk, the composite risk factor may be a practical approach to control for yet unknown risk variables in Alzheimer’s disease research. Many studies investigating healthy people at risk for Alzheimer’s disease focus on single risk factors, such as the APOE-4 allele. This could result in both overestimation and masking of APOE-4 related effects. For clinicians, these data could be useful to avoid oversimplifying assumptions about APOE-4 genetic risk. APOE is a remarkable susceptibility gene, but the extensive literature on APOE could reduce the awareness for other important risk conditions and their influence on brain function including other genetic factors as well as modifiable environmental risks. Studies show that, for example, vascular risks may contribute to the family history risk factor. Strategies aimed at enhancing vascular health could be important for the prevention of Alzheimer’s disease (Luchsinger 2008
). This should encourage clinicians to proactively educate and advise their patients.
Dubois and colleagues (2007)
proposed revised research criteria that require significant episodic memory impairment and the presence of supporting biomarkers to diagnose Alzheimer’s disease. This specifically acknowledges the potential of today’s biomedical research techniques to help establish a diagnosis as early as possible. Multimodal neuroimaging could help to determine changes in brain morphology and function that may occur as a result of risk factors, aging, and neuropathology. These data, in concert with CSF and neurocognitive variables, could be helpful to establish prediction models for future cognitive decline. From a clinical perspective it is important to know how and how much dementia risk conditions contribute to brain structure and function changes. This could determine the subjective weight we may attribute to risk factors in clinical evaluations, which ultimately influences clinical decisions. If we examine the APOE genotype status, we do not disclose this information to our patients. Because of the substantial amount of available APOE research data we believe in the impact an APOE-4 allele may have, although the risk allele is not sufficient to cause the disease or to fully determine its clinical course. The family history risk factor may be useful to account for yet unknown genetic and perhaps non-genetic risks for Alzheimer’s disease. Across various fields of investigation recent data show remarkable effects associated with this risk factor. For family history risk there is no disclosure we could chose to avoid, but this should not prevent us from recognizing it’s value in Alzheimer’s disease research and clinical practice.