The common feature of all the dementias is multiple cognitive deficits that include severe memory impairment, and at least one of the following cognitive disturbances: aphasia (deterioration of language function); apraxia (impaired ability to execute motor activities despite intact sensorimotor function); agnosia (failure to identify objects despite intact sensory function); or disturbance in executive function (the ability to reason, "plan and execute complex behaviour) (DSM-IV 1994). Severe memory impairment in the absence of other cognitive disturbances is "amnesia. Hence demented patients suffer from amnesic disturbances, but 'global amnesics' with selective mediotemporal and telen-cephalic lesions are not demented. Dementia usually displays insidious onset and progressive exacerbation of symptoms. The dementias are differentiated on the basis of their aetiology (Fraser 1987; Edwards 1993; Knopman 1993; DSM-IV 1994; Larson and Imai 1996). The most prevalent (> 30%) is Alzheimer's disease (AD) (see below). Other prevalent causes of dementia are: cerebrovascular accidents (vascular or multi-infarct dementia, 15-20% of cases); chronic alcoholism; head trauma; Parkinson's disease; Huntington disease; Pick's disease; Creutzfeldt-Jacob disease; and complications of AIDS. The incidence of dementia increases with age. Estimates for the prevalence of dementia are 2-10% at >65 years of age, increasing to 20-40% at >80 years of age (Jorm et al. 1987; DSM-IV 1994; Price and Sisodia 1998). Dementias that become apparent at <65 years of age are termed 'early-onset'; those that become apparent later are 'late-onset' or 'senile'.
In many societies there is a remarkable shift toward extended life expectancy. Therefore, diseases of old age that were rarely encountered only a century ago are now becoming an epidemic. In 1900, less than 1% of the world's population was over 65 years of age, in 2000, it was already about 7%, and the predication for 2050 is 15-20% (Olshansky et al. 1993; Heilig 1997). The main concern is AD. Named after the physician who first described it (Alzheimer 1907), it typically starts with significant recurrent lapses of "episodic ("declarative) and "prospective memory. At first impaired encoding is possibly more significant than increased "forgetting (Granholm and Butters 1988), and "metamemory is relatively spared (Moulin et al. 2000). The disease progresses to severe global memory deficits accompanied by other cognitive and emotional disturbances, and culminates in dissolution of personality and inability to perform even the simplest of tasks (McKhann et al. 1984; DSM-IV 1994). AD destroys the "hippocampal formation, neo"cortex, basal forebrain, and additional brain organs and circuits. The affected brain displays two distinguishing pathologies: extracellular plaques and intracellular tangles. The plaques are extracellular deposits of aggregated insoluble fragments of proteins (peptides), called the P-amyloid peptides (APP). The ApPs are cleaved by enzymes, secretases, from the extracellular segment of a larger membrane protein, the amyloid precursor protein (APP), which normally plays a role in cell-cell and cell-matrix interactions. Tangles are intracellular deposits of hyperphosphorylated tau proteins, constituents of the cellular skeleton (Kosik 1994; Edelberg and Wei 1996).
We do not yet understand AD, but some candidate cellular clues are already available. One line of incriminating evidence points to the severe loss of cholinergic neurons (i.e. neurons that secret "acetylcholine) that is detected in the basal forebrain of AD patients (Bartus et al. 1982;McGeer et al. 1984). As acetylcholine is proposed to subserve widespread cognitive functions, the hypothesis was raised that cholinergic dysfunction is the cause of dementia. Furthermore, as there is some decline in cholinergic function even in normal ageing subjects, the suggestion was further made that all dementia, including modest, 'benign' senile dementia, result from cholinergic deficits; and that in AD, the number of cholinergic neurons is reduced below a threshold (<25%, McGeer et al. 1984) that is required for minimal cognitive function. This is 'the cholinergic hypothesis' of dementia. Drugs that increase the availability of acetylcholine in brain were introduced as cognitive boosters in early stages of AD, so far with modest success (Giacobini and McGeer 2000; also "nootropics). Actually, nicotine, an activator of some acetylcholine "receptors, may be the only real reason why smokers could justify their addiction (e.g. Di Carlo et al. 2000; but smokers should not feel good about it, because smoking reduces pulmonary function, depriving the brain of oxygen and impairing cognition; Emery et al. 1997). The beneficial impact of cholinergic activators on memory is possibly due to their effects on arousal, "attention, and "performance (Everitt and Robbins 1997), rather than memory per se.
Another type of potential breakthrough in understanding AD was made possible by "neurogenetics.1 AD occurs in two main forms. Some variants of the disease, mostly early-onset, propagate in families ('familial AD'). Other, late onset variants, occur sporadically in the general population ('sporadic AD', 'senile dementia of the AD type'). Familial AD provides an opportunity to hunt AD-related mutations. Some were indeed identified (Goate et al. 1991; Edelberg and Wei 1996; Levi-Lahad and Bird 1996; Hardy et al. 1998; Price and Sisodia 1998). To date, familial AD has been linked to mutations in three genes, that encode APP, presenilin-1 (PS1) and presenilin-2 (PS2). APP is the amyloid precursor protein mentioned above. The presenilins are membrane proteins thought to affect the activity of the secretases that act on APP and lead to accumulation of the insoluble APPs in plaques. An additional gene, encoding apolipoprotein E (ApoE), is related to the aetiology of AD. Together with other lipoproteins, ApoE plays a part in the metabolism and transport of cholesterol and triglycerides. One of its forms, ApoE4, has been associated with increased susceptibility to sporadic, late-onset AD. ApoE4 interacts with APPs and tau (Edelberg and Wei 1996). The identification of mutations that comprise a risk factor in AD has led to a number of genetic "models of AD in mice (Price et al. 2000). The relevance of these animal models to the human AD pathology must yet be established (e.g. Janus et al. 2000).
So what triggers AD? Some authors trust that the amyloid cascade is to be blamed (Hardy et al. 1998). Others favour the idea that the pathology is initiated elsewhere, and that the plaques and tangles ensue. It is noteworthy that in the mouse, a genetic trick that reduces nerve growth factor and basal forebrain cholinergic activity, gave rise to age-dependent appearance of amyloid plaques and neurofibrillary tangles in the cortex and hippocampus (Capsoni et al. 2000). This raises the possibility that lack of growth factors induces AD-like neurodegeneration. However, again, the relevance to the human disease is unclear. Such research is of great interest not merely because it is expected to explain how AD happens, but also because it could identify drugs to prevent the catastrophe. Interestingly, an almost forgotten hallmark of AD, local inflammatory response to plaques, tangles, and neuronal degeneration (Rogers et al. 2000), has recently gained renewed interest: certain nonsteroidal anti-inflammatory drugs retard the symptoms of AD (Giacobini and McGeer 2000). After all this sophisticated molecular biology, we may end up swallowing aspirin to combat senility (the reader is strongly urged not to regard this as a practical advice).
Does AD research contribute to memory research? To answer that, we must separate memory from "plasticity. The contribution to memory research per se is there, but limited. AD is not a memory-specific pathology. In this respect, it is different from the "amnesic syndrome, or from circumscribed dementias that result from degeneration to localized brain foci (e.g. Graham
1999). Indeed, the analysis of AD does corroborate the preferential role of the "cerebral cortex, hippocampus and basal forebrain in memory. The observation that in AD, event memory is typically degraded before fact memory, and declarative before procedural memory, provides additional support to the conventional "taxonomy of memory systems. But the major contribution of AD research, and dementia research in general, is expected to be in the field of "plasticity, including the role of inter- and "intracellular signalling cascades in plasticity. This is because the common denominator of all dementias might be a catastrophe of neural plasticity (Mesulam 1999; Bothwell and Giniger
2000). Seen this way, dementia could be the heavy price we risk paying at old age for our ability to learn so efficiently throughout life.
Selected associations: Acetylcholine, Attention, Plasticity, Real-life memory
'Neurogenetics has contributed in recent years to the identification of risk factors of some other dementias as well (e.g. Garcia and Cleveland 2001).
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