Descriptions of the aetiology of neurodegenerative disorders often focus on their specific molecular and genetic basis of archetypical phenotypes. Clinical trials usually focus on unequivocal and unconfounded cases, through strict inclusion and exclusion criteria. This is understandable in terms of clarity of didactic teaching, and clinical trial efficiency. However, comorbidity is the norm, not the exception.

The advent of biomarkers highlighted the pre-symptomatic stage of neurodegenerative disease, among apparently healthy adults with normal cognition (Figure 10.3.1A). This preclinical stage comes before the period of mild early symptoms and signs, which is called the prodromal phase. With genetic aetiology, one can study healthy pre-symptomatic adult mutation carriers many years before symptoms. This is underway through international collaborations such as the Dominantly Inherited Alzheimer Network, the Genetic Frontotemporal Dementia Initiative and Parkinson’s Progression Markers Initiative genetic cohort. These international collaborations have much in common, with large cohorts (500–1,500) of patients and healthy first-degree relatives; followed longitudinally with ‘deep phenotyping’ of multiple blood, cerebrospinal fluid and imaging biomarkers and neuropsychological evaluation.

We have seen that there is a long period of neurodegeneration in the absence of symptoms. This asymptomatic period highlights the issues of functional reserve, resilience and tolerance – that function (cognition, activities and roles etc.) can be maintained despite pathology (molecular pathology, neuroinflammation, synaptic loss, atrophy).

The burden of dementia on health, social and economic well-being is enormous, whether viewed in terms of the 40 million people living with dementia (predicted 75 million by 2030) or the trillion-dollar cost per annum (predicted $2 trillion by 2030) [1]. In many parts of the world, mental health services provide the backbone to dementia diagnosis and management. The sections in this chapter focus on neurodegenerative disorders although several non-degenerative causes of dementia are considered alongside. Neurodegenerative disorders commonly present with changes in personality and behaviour that lead to referral for psychiatric assessment. Other common psychiatric disorders can mimic dementia, or complicate its management.

The syndromes caused by Alzheimer’s disease pathology, dementia with Lewy bodies, frontotemporal lobar degeneration and progressive supranuclear palsy pathology are each diverse. For example, Alzheimer’s disease commonly presents with amnesia (and hippocampal atrophy), but it can also present with visuospatial deficits (posterior cortical atrophy), logopenic progressive aphasia (temporoparietal atrophy), corticobasal syndrome (parkinsonism, dystonia, apraxia and higher cognitive deficits) or a behavioural/dysexecutive syndrome [52].

The dichotomy of dementia diagnosis (healthy adult versus patient) conflicts with the gradually progressive nature of neurodegeneration. There may be a memorable first event – such as a fall, or getting lost – but usually symptoms emerge against an individual’s normal ability and behaviour. In other words, they start mild.

In the seminal report of the Lancet Commission on dementia [54] the identification of contributory risk factors, their effect size and their modifiabilty, led to a startling conclusion: as much as 40% of dementia could be prevented by immediate application of known interventions. Not by a novel disease-modifying treatment but a systematic approach to resolve and reduce risk factors across the lifespan. Early-life education; mid-life obesity, hypertension and hearing loss; and later life exercise, smoking, social isolation, diabetes, depression and pollution contribute to this potential for dementia prevention.