The consensus on neurodegenerative diseases, particularly Alzheimer's disease, is coming to be that these varied age-related conditions have deep roots. People on the road to developing Alzheimer's most likely have a biochemistry that is distinguishable from their peers ten or twenty years prior to the emergence of evident symptoms, and perhaps even earlier. The open access paper noted here discusses some of the evidence that supports this viewpoint.
Along these lines, I think that we will see a sizable growth in efforts to find early biomarkers that predict later development of neurodegeneration, building on the work of recent years in which the first few comparatively non-invasive approaches have appeared in the literature. It remains unclear at this time as to the degree to which lifestyle choices matter in these considerations. While there are certainly arguments for Alzheimer's risk to be increased by being sedentary and overweight, one of the biggest questions regarding Alzheimer's is why only some people with these risk factors go on to develop the condition rather than the majority one might expect in the case of a strong causal relationship.
Alzheimer's disease (AD) accounts for around 60-80% of dementia cases, and its symptoms are projected to affect greater numbers of people every year. Insidious and irreversible memory decline is the most recognized feature of AD, beginning with initial short-term memory deficits that make learning new information difficult, but other areas of cognition such as word-finding and executive function can also decline. As a patient progresses through mild, moderate, and severe stages of AD, greater memory deficits, increased confusion, and personality and behavioral changes, among other symptoms, are frequently observed and lead to round-the-clock assistance needs with everyday activities.
The precise brain mechanism affected by neural degeneration in the earliest stages of AD is still largely hypothesized. Recent evidence suggests that various subcortical brain nuclei may show the first AD-related pathology. The transentorhinal region is thought to be the first affected site in the cerebral cortex, and in later stages of the disease, atrophy spreads throughout cerebral cortex association areas. The question of when and in what ways healthy aging diverges from the incipient AD remains poorly understood and the focus of active research, with very recent research suggesting that this divergence may be observed as early as midlife. The identification of pathological aging in midlife could be transformational. The brain is thought to be modifiable in neural and cognitive ways, so early detection and intervention could lead to improved treatment and, ultimately, prevention of Alzheimer's dementia.
Before dementia's symptoms occur, an intermediate stage of mild cognitive impairment (MCI) may occur. MCI can be a transitional stage between normal aging and dementia, but not all people who experience it will develop dementia. MCI is characterized by observable cognitive deficits that resemble, but are less severe than, those typical of different dementias. Particularly in AD, pathophysiological processes leading to the disorder may have already begun an irreversible trajectory of neurodegeneration by the stage of MCI, as several studies suggest that dementia's pathology may be present years or even decades before its clinical diagnosis. Intervention prior to the development of MCI thus may be necessary to significantly reduce dementia incidence. However, the early divergence of healthy and pathological aging remains elusive.
Associations have been found between higher risk for AD and greater midlife decline in episodic memory and executive function. Other evidence may suggest, however, that trends in visuospatial ability deficits more strongly differentiate healthy vs. pathological aging in midlife. Other cognitive domains such as attention and language abilities have not yet displayed substantial differences in middle-aged individuals of varying dementia risk.
In addition to cognitive markers, structural neuroimaging has shown diverging trends in gray matter reduction and loss of white matter integrity in healthy vs. pathological aging. Healthy aging is more strongly associated with decline in frontal regions, while middle-aged individuals more likely to develop AD have shown greater gray matter reductions and loss of white matter integrity. Additionally, midlife volumetric reductions in the fronto-striatal executive network seem to be a normal part of aging, while reductions in the medial temporo-parietal episodic memory network seem to indicate pathological aging. Finally, entorhinal cortex and hippocampal atrophy rates appear to diverge in healthy and pathological brain aging, but it is not yet known if this divergence is relevant to midlife.