#BrainHealth: when does ageing become a disease?

Should we redefine ageing as a disease? #BrainHealth #ProfG #HealthyAgeing

Most of neurologists equate amyloid deposition in the brain with Alzheimer's disease (AD). This study questions this assumption and suggests that amyloid deposition is simply a part of normal ageing. Demographics, the APOE genotype and midlife dyslipidaemia was associated with amyloid deposition. In comparison obesity, smoking, diabetes, hypertension, and cardiac and metabolic conditions, but not intellectual enrichment, were associated with greater AD-pattern neurodegeneration. 

These results in elderly individuals supports the hypothesis that tackling common lifestyle factors obesity, smoking, diabetes, hypertension, and cardiac and metabolic conditions could prevent, or at least, delay the onset of symptomatic AD and is consistent with the falling incidence of AD in both the Cambridge and Framingham cohort studies. 

Please note that although the incidence (number of new cases per 100,000 people in the general population) of AD is falling, the prevalence (total number of people living with AD per 100,000 people in the general population) is increasing. This is particular problem in countries with an ageing population and is the reason why AD, and in particular all-cause dementia, is referred to as 'the ticking time-bomb'. 

The philosophical debate that underpins these observations is the question of whether or not we should define normal ageing as a disease. Finding amyloid deposits, a putative biomarker of disease, in 'normal people' challenges that assumption. This debate is not new, but it is something society needs to get a grip on if we are to have an impact on reducing the burden of dementia on society. 

Vemuri et al. Evaluation of Amyloid Protective Factors and Alzheimer Disease Neurodegeneration Protective Factors in Elderly Individuals. JAMA Neurol. 2017 Apr 17. doi: 10.1001/jamaneurol.2017.0244

IMPORTANCE: While amyloid and neurodegeneration are viewed together as Alzheimer disease pathophysiology (ADP), the factors that influence amyloid and AD-pattern neurodegeneration may be considerably different. Protection from these ADP factors may be important for aging without significant ADP.

OBJECTIVE: To identify the combined and independent protective factors for amyloid and AD-pattern neurodegeneration in a population-based sample and to test the hypothesis that "exceptional agers" with advanced ages do not have significant ADP because they have protective factors for amyloid and neurodegeneration.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study conducted a prospective analysis of 942 elderly individuals (70-≥90 years) with magnetic resonance imaging and Pittsburgh compound B-positron emission tomography scans enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive aging in Olmsted County, Minnesota. We operationalized "exceptional aging" without ADP by considering individuals 85 years or older to be without significant evidence of ADP.

MAIN OUTCOMES AND MEASURES: We evaluated predictors including demographics, APOE, intellectual enrichment, midlife risk factors (physical inactivity, obesity, smoking, diabetes, hypertension, and dyslipidemia), and the total number of late-life cardiac and metabolic conditions. We used multivariate linear regression models to identify the combined and independent protective factors for amyloid and AD-pattern neurodegeneration. Using a subsample of the cohort 85 years of age or older, we computed Cohen d-based effect size estimations to compare the quantitative strength of each predictor variable in their contribution with exceptional aging without ADP.

RESULTS: The study participants included 423 (45%) women and the average age of participants was 79.7 (5.9) years. Apart from demographics and the APOE genotype, only midlife dyslipidemia was associated with amyloid deposition. Obesity, smoking, diabetes, hypertension, and cardiac and metabolic conditions, but not intellectual enrichment, were associated with greater AD-pattern neurodegeneration. In the 85 years or older cohort, the Cohen d results showed small to moderate effects (effect sizes > 0.2) of several variables except job score and midlife hypertension in predicting exceptional aging without ADP.

CONCLUSIONS AND RELEVANCE: The protective factors that influence amyloid and AD-pattern neurodegeneration are different. "Exceptional aging" without ADP may be possible with a greater number of protective factors across the lifespan but warrants further investigation.