Molecular Psychiatry (1997) 2, 21–25  1997 Stockton Press All rights reserved 1359–4184/97 $12.00

PERSPECTIVE Does Alzheimer’s disease start early in life? TG Ohm

Institut fu¨r Anatomie, Charite, Humboldt-Universita¨t, 10098 Berlin, Germany

Aging and Alzheimer’s disease are two of the keynotes of our time. Since its first description by Aloys Alzheimer about 90 years ago, this neurodegenerative condition has advanced to become the fourth most common cause of death in the elderly, and is found in more than half of the very elderly demented. Despite new findings which are linked to several aspects of Alzheimer’s disease, relatively little progress has been made toward the discovery of reliable methods for early diagnosis or the development of a successful therapy for this debilitating disease. It is therefore helpful to recall the major underlying questions related to our under- standing of the pathogenesis of Alzheimer’s disease. This article deals with two of these: What is the earliest stage at which we can diagnose the disease? What influences the onset and progression of the disease? As simple as these questions appear to be, attempts at answering them show us the complicated, multi-facetted face of Alzheimer’s disease. Keywords: Alzheimer’s disease; aging; development; stages; therapy

Despite recent progress, Alzheimer’s disease remains mer’s disease-predictive mutation product is, on its one of the most enigmatic diseases of the last decades. own, not necessarily sufficient to cause the disorder It challenges our society from both a medical and a and/or disorder-related histological changes. Three socio-economic perspective. Since its discovery by the major classes of histological alterations can be detected German neurologist and neuropathologist Aloys Alzh- in a typical Alzheimer-brain. The first of these are the eimer about 90 years ago, Alzheimer’s disease has formation of A4-amyloid, deposited as congo-red-nega- come to account for the majority of senile dementia tive diffuse plaques, congo-red-positive ‘mature’ amy- cases and has become the fourth most common cause loid plaques and/or congophilic amyloid angiopathy. of death among the elderly. In most cases, approxi- All three forms of amyloid deposition are located in mately a decade will pass between diagnosis and death the extracellular space. Secondly, we find intraneu- and for much of this time, the patient will require a ronal changes of the cytoskeleton. Hyperphosphoryl- 24-h care service. A curative treatment is not cur- ated microtubule-associated protein tau (A68, PHF-tau) rently available. forms straight and paired helical filaments (PHF). The efforts poured into genetic analysis of Alzhei- Light-microscopically these aggregates of hyperphos- mer’s disease unveiled several mutations. However, phorylated tau protein appear as neuropil threads (in these mutations account for only a small minority of dendrites), neuritic plaques (often around an amyloid familial cases (about 5%).* Usually, these mutation- core) and neurofibrillary tangles (in the soma). The related familial cases exhibit an early clinical onset of presence of extracellular neurofibrillary tangles (‘ghost the disease. This is in contrast to the vast majority of tangles’) points to neuronal death. Thirdly, neuronal Alzheimer patients, who carry no predictive genetic and synaptic loss takes place, the degree of which is marker, and whose clinical symptoms do not show up quite possibly an anatomical correlate for the cognitive until later in life. decline. It is conceivable that a slow and negligible Transgenic animals expressing human amyloid pre- synaptic loss can be compensated by the central ner- cursor protein (APP), even those with a known Alzh- vous system, which has considerable capacity in terms eimer-mutation, do not develop the typical histopatho- of redundancy and plasticity. Neurofibrillary changes logical picture of an Alzheimer-brain, although some occur only in highly specified cells of particular areas amyloid deposition does take place. From this, we of the brain, eg primarily in the entorhinal cortex but might deduce that the over-expression of an Alzhei- not in the cerebellum. The typical pattern evolves gradually over time and is more likely to reflect vari- ations in susceptibility rather than direct anatomical Correspondence: TG Ohm, MD, Institut fu¨ r Anatomie, Charite, connectivity. With regard to the region- and cell type- Humboldt-Universita¨t, 10098 Berlin, Germany. E-mail: tgohm specific formation of Alzheimer’s disease-related histo- Ȱrz.charite.hu-berlin.de logical changes in patients’ brains, the importance of * Editor’s note: See the article by Sandbrink and Beyreuther the constitution of the ‘host’ (in terms of both cell- or (pages 438–444) in the December 1996 issue of Molecular Psy- chiatry for the latest advances on the molecular biology of presen- species-specificity) might be of currently underesti- ilins in familial Alzheimer’s disease. mated relevance. Received and accepted 6 November 1996 It is important to recall some of the more general Does Alzheimer’s disease start early? TG Ohm 22 questions related to the understanding of a disease and speaking, the full blown histopathological picture of to evaluate progress toward answering these. Among Alzheimer’s disease is reached more than four decades the many important issues, there are two questions of after development of the initial tangle. At present, it is major relevance with respect to both diagnosis and only the last decade of Alzheimer’s disease which can therapy. The first deals with the differentiation be clinically diagnosed using routine neuropsycholog- between normal aging and pre-clinical stages of the ical assessment. The first four decades escape normal disease: What are the first signs of a long and slowly neuropsychological detection. Usually, Alzheimer’s developing disease? This seemingly simple question disease is diagnosed clinically 3 years after onset of the can be separated out into several further questions: first symptoms and there is an average interval of 5 How can we distinguish between clinical and non- years between diagnosis and death. The concept that clinical, eg pre-clinical signs? What are the first neuro- neurofibrillary tangles in the pre-clinical stages of logical, eg cognitive signs? What are the first histo- Alzheimer are indeed related to this particular dis- pathological features in the brain? Do they develop in ability and are not ‘normal’ has a further implication: parallel to neuropsychological data or is there a long neurofibrillary tangles are now regarded as highly spe- pre-clinical period? And, are there non-cerebral alter- cific signs of a disease. The presence of neurofibrillary ations indicating that Alzheimer’s disease is a more tangles in Parkinson’s disease, dementia pugilistica etc general disorder with only a clinical focus on the are no longer interpreted as unspecific but as signs of brain? co-morbidity. It is possible for an individual to have both Parkinson’s disease and Alzheimer’s disease, the latter, however, in a pre-clinical state. The pre-clinical phase of Alzheimer’s disease The second line of evidence stems from results of Most disorders, unequivocally the degenerative ones, the nun study.2 This investigation provides evidence usually have a pre-clinical phase. In order to detect this which indicates that the level of linguistic ability in pre-clinical stage, at least one specific marker must be early life, ie in the twenties, correlates with the inci- known. Today, the clinical diagnosis of Alzheimer’s dence of Alzheimer’s disease in later life, in what is disease is presumptive until neuropathological exam- an otherwise extremely homogenous group of females. ination of the brain takes place at autopsy. The contem- (Low linguistic expressive ability equals a higher risk porary paradigm however, ie the histopathological in terms of Alzheimer’s disease.) The authors hypoth- diagnosis, depends on markers demonstrating neuro- esise that subtle brain changes, for example, minor fibrillary tangles and senile plaques in sufficiently high neurofibrillary changes, must take place early in life. numbers. Lower number, particularly in individuals However, since it is not yet definitively known whether with no clinical signs of the disease, are usually low linguistic ability is in fact related to an early histo- regarded as so-called normal age-associated neurofib- pathological expression of neurofibrillary changes, rillary changes of the Alzheimer-type. Recent research further studies are required. An alternative explanation supports more and more the concept that the demon- for the correlation between low linguistic ability and stration of the very first neurofibrillary tangle is already Alzheimer’s disease in later life would be compatible the beginning of Alzheimer’s disease. Evidence for this with a reduced degree of plasticity of the neuronal net- comes from two completely independent angles: the work. This would lead to reduced functioning in sev- analysis of staged autopsy brains and the results of the eral cognitive functions and is also quite likely to be elegantly designed and reputed nun study. associated with a reduced repair capacity of the ner- In the first study, several hundred brains were staged vous systems, which might conceivably lead to the for- at autopsy according to the degree of neurofibrillary mation of neurofibrillary changes. Apolipoprotein E, tangles—a major histopathological hallmark of Alzhei- with one isoform being a major risk factor for late onset mer’s disease—they displayed. The ensuing analyses Alzheimer’s disease, is assumed to play an important suggested strongly that Alzheimer’s disease begins role in development and re-organisation of neurons. A more than four decades before routine neuropsycholog- high expression of this protein takes place during ical assessments are able to diagnose the disease.1 The ontogeny, when neurons differentiate and neuronal approach was based on the well-supported assumption networks are becoming established. Thereafter, there is that there is no principal difference between a neuro- a considerable decline in apolipoprotein E expression fibrillary tangle developed in clinically inconspicuous until lesions of the central nervous system evoke a re- individuals and individuals showing clinical signs of expression.3,4 Experimental studies have already Alzheimer’s disease. Consequently, the discovery of shown that apolipoprotein-E4, the risk factor for late neurofibrillary tangles in clinically inconspicuous onset Alzheimer’s disease, is also associated with nega- individuals is now no longer regarded as a sign of nor- tive neural effects, including a reduction in neurites, mal aging but as an antecedent of a prolonged pre-clini- both in number and geometry.5 Thus, it cannot be ruled cal phase. In this respect, the development of Alzhei- out that the various apolipoprotein E isoforms act dif- mer’s disease compares to the development of cancer. ferentially on cellular plasticity even during normal Here, the clinically inconspicuous carcinoma in situ is ontogeny. Unfortunately, the apolipoprotein-E status of not regarded as part of normal aging, but accepted as the nuns under consideration is not reported. Inclusion the pre-clinical stage of a slowly progressing disease. of this criterion in the study might have shed some In line with this view, we can now say that, statistically light on this avenue of exploration; whether low Does Alzheimer’s disease start early? TG Ohm 23 linguistic ability and the development of Alzheimer’s with the major and broad prevalence peak of Alzhei- disease is associated with a reduction in the plasticity mer’s disease, ie the late onset form. If we could under- of the central nervous system. Ongoing studies on the stand the underlying molecular mechanism by which dendritic features of young individuals without clini- the respective Apolipoprotein E isoforms—which, in cal signs of Alzheimer’s disease but with different apo- the brain, are produced solely in glial cells—influence lipoprotein alleles, will reveal whether this is the case the onset of the disease and thus neuronal functioning, in vivo. it might be possible to develop a completely new thera- One of the main problems with the early detection peutic strategy. An intervention which enables a shift and diagnosis of Alzheimer’s disease-related changes in the prevalence peak of Alzheimer’s disease by only is the difficulty of correlating pre-clinical alterations 5 years after the peak of our mean life time will reduce in the brain in vitro with detectable changes in vivo. the absolute numbers of Alzheimer patients by 50%.16 Currently, even extremely sophisticated in vivo neuro- An accompanying effect of this would be to drastically radiological imaging techniques stay within the limits reduce the tremendous costs necessary for nursing and of a 5-mm2 resolution. A cortical volume of this size, medical care. These are costs which, under present cir- however, contains millions of nerve- and glial cells, cumstances, will rise dramatically in western societies and in the early stages of the disease, only few of these within the next three decades, as the relative pro- are likely to be altered. Only recently, cerebrospinal portion of individuals aged 65 and over develops from fluid (CSF) diagnostics using antibodies raised against its present level of 1 in 5 of the total population to 1 Alzheimer-tau,6 provided a new instrument for the in 3. Unfortunately, the present pharmacotherapeutic detection of mild cases of Alzheimer’s disease. How- intervention strategies only exert their beneficial ever, PHF-tau is not secreted, but is rather the result of influence over a relatively short period of time; ie 1–2 a considerable nerve cell loss. Therefore, it is unlikely years, after which a considerable decline in cognitive that the detection range will be significantly different capacity takes place. from the neuroradiological approaches in terms of Available evidence suggests that the apolipoprotein identification of very subtle and pre-clincial states of E isoforms have a differential effect on both of the the disease. Another recently proposed approach, the classic neuropathological features of Alzheimer; the measurement of pupil dilatation, seems not to dis- extracellularly located amyloid deposition and the criminate well enough between Alzheimer’s disease intraneuronally situated tau-pathology.15,17 Apolipo- and other conditions, especially in younger people.7 It protein E4 increases the formation of amyloid plaques may be possible to overcome this detection threshold whereas apolipoprotein E2 decreases the deposition, and other problems if: (i) there is a non-cerebral change both in comparison to the ‘wildtype’ apolipoprotein taking place in blood cells or other body tissues which E3. With regard to the impact of the apolipoprotein E is specifically related to the progression of the disease; polymorphism on the formation of the tau-pathology, and (ii) this is detectable even in pre-clinical states ie the formation of neuropil threads and neurofibrillary with methods involving a higher degree of sensitivity tangles, this opposing effect of the E2 and E4 isoforms than the current neuroradiological and neurological is not absolutely clear. Autopsy analyses provided evi- techniques, eg CSF-diagnostics. The main assumption dence that the apolipoprotein E4 brings forward the behind this approach is that Alzheimer’s disease is a beginning of tau-pathology, although the spread or pro- much more general disorder and that cerebral dysfunc- gression of neurofibrillary tangles and neuropil threads tion is only the most prominent and conspicuous fea- throughout the cortex is not changed. Again, this is in ture of the ailment. Indeed, there is some evidence of comparison to the homozygotic E3 allele carriers.15 An cells outside the central nervous system being involved interesting observation was made regarding the age- in Alzheimer’s disease.8–12 Moreover, if a mutation in and gender-matched individuals who were staged for APP can cause Alzheimer’s disease, then the questions amyloid deposition. It was observed that in the remain: (a) what causes this mutation in other APP- apoE2/3 or apoE2/2 constellations, neurofibrillary expressing cells of the body; and (b) is this effect changes seem to start later but proceed faster than in detectable before the neuropsychological detection of the apoE3/3 individuals (unpublished observations).18 the clinical stages of Alzheimer’s disease takes place? From these results, we conclude that, first, the apolipo- APP has been shown to be expressed in muscle, testis, protein E isoforms, differing from each other on the and other tissues,13 some of which are clinically avail- basis of one amino acid only, seemingly act on two tot- able for biopsy. ally unrelated molecules, APP and tau. Both, however, are pathologically processed in Alzheimer’s disease and their changes eventually lead to the formation of Time course of Alzheimer’s disease the diagnostic histopathological gold standards: pla- The next major question is more therapy-related: What ques and tangles. This implies that a risk factor, which modulates the onset and the progression of Alzhei- may be effective in more than 80% of late onset cases mer’s disease? An important and exciting new finding of Alzheimer’s disease, is likely to act on a metabolic was the demonstration that the various Apolipoprotein intermediate or effector common to both APP and tau. E alleles are capable of postponing the onset of the dis- Interestingly, we now have first evidence that apolipo- ease by more than 10 years.14,15 At present, the average protein E3 can not bind to tau when tau serine 262 is life expectancy is around 78 years, which is coincident phosphorylated.19 The alternative is that apolipopro- Does Alzheimer’s disease start early? TG Ohm 24 tein E exerts its influence on two completely different involved in Alzheimer’s disease, associated with a intermediates or effectors which share a common apo- slowly progressing spread of Alzheimer’s disease- lipoprotein interaction site. There is a third, somewhat related neurofibrillary changes, then the duration of the unlikely possibility, that either pathological APP pro- shift between selected stages represents a measure by cessing or hyperphosphorylation of tau induces the for- which risk and beneficial factors can be identified. A mation of the respective other. One reason for this possible risk factor should shorten this time even if the skepticism is that there are ‘tangle only’ individuals cohort under evaluation dies at an age too early for who display large amounts of amyloid deposition in clinical signs, and an effective drug treatment or ben- the absence of the tau pathology cases.20–22 Another eficial factor should delay this period. reason is, that apolipoprotein E2 seems to act differen- tially on amyloid and tangle formation whereas apoli- poprotein E4 exerts an equidirectional influence on Conclusion both of these hallmarks.23 An accumulation of clinical and neuropathological evi- dence would seem to indicate that Alzheimer’s disease Future approaches begins early in life. This presents the medical research community with considerable diagnostic difficulties, As long as we are unable to identify very small as the only reliable assessment tool for detection of the accumulations of neurofibrillary changes (in a magni- very early stages of the disease is neuropathological tude of tens or a hundred) or beginning amyloid depo- assessment. Careful prospective studies of families sition in living patients, a direct correlation to non-cer- with a mutation predictive for Alzheimer’s disease pro- ebral biological markers is impossible. The detection of vide chances for the detection of non-cerebral alter- diagnosis-relevant peri- and/or postmortally unaltered ations associated with Alzheimer’s disease. Correlation biological parameters which will allow a direct corre- of identified non-cerebral changes in vivo with neuro- lation to the neuropathological status of the brain is, pathological stages at autopsy in age groups throughout however, very unlikely. One slightly more promising the life span (including very young individuals) may strategy with a greater likelihood of finding a pre-clini- help us find early biological markers of the disease. cal marker is the careful follow-up screening of biologi- Continuing research into the early detection and poss- cal markers in individuals who are clinically still ible therapy of Alzheimer’s disease is of paramount inconspicuous, but come from families with a known importance to all modern societies in which fewer chil- predictive mutation for Alzheimer’s disease. Another dren are being born and increased longevity is rapidly probable approach is related to our knowledge of the creating a large community of aged persons – potential fact that fibroblasts are relatively resistant to hypoxia. victims of Alzheimer’s disease. Without research into A rapid autopsy programme might allow us to obtain Alzheimer’s disease and the ensuing advances in some fibroblasts which could subsequently be main- understanding, the few young in this population struc- tained under cell culture conditions over a longer per- ture may, in the medium-to-long-term, have neither the iod of time, for use in in vivo experiments. The respect- physical nor financial resources to support and care for ive brain status would be directly available for a the increasing numbers of those afflicted with Alzhei- correlative analysis. Pilot studies on post-mortem rat mer’s disease. Earlier diagnosis means a lesser degree tissue suggest that this is a feasible possibility of cerebral destruction and a greater chance for effec- (unpublished observation). tive therapeutic interventions. Early detection and a The methods used to detect risk – or beneficial fac- therapeutic approach which can, at least, delay the tors (the latter also including therapeutic drugs) for onset of Alzheimer’s disease by 5 years, would fulfil Alzheimer’s disease, are usually based primarily on the the dual functions of giving the elderly more quality of analysis of onset, progression or duration of clinically life and of easing one of the many social challenges diagnosed individuals. In these studies, the role of facing western society at the advent of the 21st century. autopsy is only that of an act which confirms the diag- nosis of Alzheimer’s disease. This type of epidemiolog- ical study evaluates clinical symptoms and is only suc- Acknowledgements cessful if a given potential risk – or beneficial factor is The above research was supported by grants from the not related to the death of the individual before clinical Deutsche Forschungsgemeinschaft (SFB C2, OH48/1-3, symptoms can emerge. Moreover, the effects of drug OH48/4-1), the Hertie Stiftung and the Research Com- treatments are evaluated in the end phase of a disease, mission of the Charite´. Thanks also to Susan J Letham the last 10 years of a disorder which in fact progresses for secretarial support. over several decades. Slight effects on the progression could be missed, as might responses dependent on the stage of the disease. For example, approaches requiring References intact intracellular trafficking and sorting will only 1 Ohm TG, Mu¨ller H, Braak H, Bohl J. Close-meshed preva- give reliable results if the cytoskeletal changes associa- lence rates of different stages as a tool to uncover the rate ted with the formation of neurofibrillary tangle do not of Alzheimer’s disease-related neurofibrillary changes. break down the cytoplasmic flow. Neuroscience 1995; 64: 209–217. Assuming that there is a long pre-clinical phase 2 Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Does Alzheimer’s disease start early? 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