Unified theory of Alzheimer's disease (UTAD): implications for prevention and curative therapy

Abstract

The aim of this review is to propose a Unified Theory of Alzheimer's disease (UTAD) that integrates all key behavioural, genetic and environmental risk factors in a causal chain of etiological and pathogenetic events. It is based on three concepts that emanate from human's evolutionary history: (1) The grandmother-hypothesis (GMH), which explains human longevity due to an evolutionary advantage in reproduction by trans-generational transfer of acquired knowledge. Consequently it is argued that mental health at old-age must be the default pathway of humans' genetic program and not development of AD. (2) Therefore, mechanism like neuronal rejuvenation (NRJ) and adult hippocampal neurogenesis (AHN) that still function efficiently even at old age provide the required lifelong ability to memorize personal experiences important for survival. Cumulative evidence from a multitude of experimental and epidemiological studies indicate that behavioural and environmental risk factors, which impair productive AHN, result in reduced episodic memory performance and in reduced psychological resilience. This leads to avoidance of novelty, dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis and cortisol hypersecretion, which drives key pathogenic mechanisms of AD like the accumulation and oligomerization of synaptotoxic amyloid beta, chronic neuroinflammation and neuronal insulin resistance. (3) By applying to AHN the law of the minimum (LOM), which defines the basic requirements of biological growth processes, the UTAD explains why and how different lifestyle deficiencies initiate the AD process by impairing AHN and causing dysregulation of the HPA-axis, and how environmental and genetic risk factors such as toxins or ApoE4, respectively, turn into disease accelerators under these unnatural conditions. Consequently, the UTAD provides a rational strategy for the prevention of mental decline and a system-biological approach for the causal treatment of AD, which might even be curative if the systemic intervention is initiated early enough in the disease process. Hence an individualized system-biological treatment of patients with early AD is proposed as a test for the validity of UTAD and outlined in this review.

Keywords: Adult hippocampal neurogenesis (AHN); Causal AD prevention; Curative AD therapy; Grandmother-hypothesis (GMH); Law of the minimum (LOM); Neuronal rejuvenation (NRJ); Unified theory Alzheimer’s disease (UTAD).

Fig. 1

“Natural mechanisms preserve lifelong mental health”. Our genetic program is well adapted to the lifestyle conditions that dominated for the largest part of humans’ life history. Ancient lifestyle was marked by extensive and daily physical activity, alternated phases of fasting and a nutrient-rich diet, sufficient sleep and eustress. Furthermore, survival was critically dependent on extended family bonds, hence went along with a rich social life. The exceptional long postmenopausal period served the purpose of transgenerational generativity, which, according to the grandmother hypothesis, provides the main current explanation for humans’ longevity. Therefore, under these natural conditions, all key physiological systems (immune and cardiovascular function, energy metabolism etc.) positively interact and thereby support key mechanisms like neuronal rejuvenation and adult hippocampal neurogenesis in order to allow the lifelong acquisition of knowledge and to preserve mental health up to high age. For details, please refer to the main text

Fig. 2

“AD is a deficiency disease”. Our genetic program is not adapted to the fast and very recent changes that define our modern lifestyle, which connotes individual combinations of physical inactivity, an ad libitum eating pattern of a nutrient-poor diet, chronic distress emanating from the demands of a highly competitive labour situation, which often goes along with a loss of extended family bonds. Furthermore and under such conditions, the concept of retirement, a late invention in humans’ cultural history, counteracts the main purpose in late life from an evolutionary point of view : A lack in transgenerational generativity leads to a devastating lack of purpose in life. Deficiencies in essential requirements for mental health cannot, by definition, be compensated by our genetic program. Consequently, as defined by the law of the minimum, individual deficits hamper neuronal rejuvenation, and in particular hinder productive AHN. As the neuronal correlate of depression, the disturbed HPA axis regulation and cortisol hypersecretion as well as other pathophysiological consequences (neuroinflammation and breakdown of the blood brain barrier, insulin resistance, hypertension and arteriosclerosis) emanate from these lifestyle-derived deficits and lead to an accumulation neurotoxic Aβ, hippocampal shrinkage in particular, and brain atrophy in general, hence the well-known hallmarks of AD. Under these conditions of behavioural deficiencies, environmental toxins, chronic infections and genetic predisposition accelerate AD progression. The indicated interactions between the different pathological processes activate a multitude of vicious cycles that make the AD-process a runaway phenomenon, which can only be stopped and reversed to the situation depicted in Fig. 1 by a systems biological approach, which is outlined in the main text and schematically presented in Fig. 3

Fig. 3

“A systems biological program for prevention and therapy of AD”. In order to support our genetic programs’ “interest” in maintaining lifelong mental health, the primary measures to prevent AD consist of a rich social life, daily new challenges which provide eustress and memorable experiences, physical activity and sufficient deep sleep, and adequate amounts of essential nutrients. As indicated by the green lines (and outlined in the main text), each of these measures have positive impacts, directly or indirectly, on key physiological systems or processes required for the preservation of mental health. In the case of an AD-diagnosis, these systems are not only compromised but, as outlined in Fig. 2 and detailed in the main text, lead to runaway phenomena. Hence, in addition to the implementation of the preventive measures and the correction of lifestyle-caused deficiencies, the proposed therapeutic interventions consist of a systemic combination of active components that were shown to interrupt the various vicious cycles that drive and accelerate the AD process. Each one was selected by its ability to interfere with a particular key pathophysiological process. But as indicated by the red lines and as outlined in detail in the main text, all of the suggested active components help to reactivate a variety of functions that are disturbed by the AD process