Overview
Clinical aspects of Alzheimer’s disease (Prof Barak). The lecture’s stated objectives are to identify a patient suffering from Alzheimer’s disease and assess their impairment, and to discuss the merits of prevention strategies; its learning headings are dementia definition, differential diagnosis, recommended approach, screening and prevention. It builds from what dementia is as an umbrella term and how common it is in an ageing New Zealand population, through separating normal ageing memory change from dementia and placing Alzheimer’s on a preclinical to MCI to dementia continuum, then into the differential diagnosis of dementia, Alzheimer’s clinical picture and neuropathology, the AT(N) biomarker classification, the newly recognised LATE syndrome, and finally why pathology alone does not explain who becomes demented: reserve, resilience, and life-course risk and protective factors. Listed resource: Malek-Ahmadi et al., Informant-reported cognitive symptoms that predict amnestic mild cognitive impairment, BMC Geriatr 2012. Linkages: none.
What dementia is
Dementia is not a specific disease. It is an umbrella term for the symptoms of a group of brain diseases that always:
- impair thought, often memory
- impair everyday activities of daily living (the critical element, emphasised on the slide)
- often involve behavioural and psychological problems
The umbrella image is the slide’s metaphor: one term covering a group of separate diseases.
Epidemiology and burden, with a New Zealand focus
- Age 65+ is the top risk factor for dementia.
- New Zealand’s older population increased slowly from about 200 thousand aged 65+ in 1951, accelerated from around 2011 as the post-war baby boomers aged (roughly 550 thousand at that point), and is projected to plateau near 1,150 to 1,200 thousand by 2041 to 2051. Over the same span the proportion of the population aged 65+ rises from about 10% to about 25%.
- About 65,000 people had dementia in New Zealand in 2016; this may be around 170,000 by 2050.
- The number of Māori kaumātua living beyond age 80 more than doubled between 2002 and 2012. Māori may present at a younger age. Better New Zealand-wide ethnicity-based dementia data is needed.
Prevalence by age (Alzheimer’s disease and related dementias):
| Age | Affected |
|---|---|
| < 60 | 0.01% |
| > 65 | 10% |
| > 85 | 25% |
| > 90 | 34% |
Other burden figures: fourth major cause of death in adults; lifespan after “onset” ranges 3 to 20 years, averaging 6 to 8 years, but with a severely truncated healthspan; 70% of dementia care is provided by families, straining the individual, whānau, society and health resources.
Normal ageing versus dementia
Memory change in ageing is not the same as the memory problem in Alzheimer’s disease or dementia. They differ in three respects:
- magnitude
- range
- context
Most normal healthy elderly people have some inconsistent problems with memory or attention, and that is normal. Alzheimer’s disease and dementia are not a normal part of ageing.
The pathological-clinical continuum
Sperling et al., 2011. Plotted as cognitive function declining over years, normal ageing follows a gradually declining curve while the Alzheimer’s course diverges downwards from it in three stages:
- Preclinical: cognition still flat and near normal.
- Mild cognitive impairment (MCI): the point where the curve separates from the ageing curve.
- Dementia: the steeply falling later portion.
Differential diagnosis: what is under the umbrella
Proportional breakdown of dementia causes:
- Alzheimer’s disease / dementia about 50%
- Vascular dementia 15%
- Mixed Alzheimer’s plus vascular 10%
- Parkinson’s and related dementia 15%
- Other, for example alcohol, HIV, CJD 4%
- Frontotemporal dementia 1%
The picture is complicated by multiple factors, genetics and age: perhaps half of those over 80 in fact have a “new” Alzheimer’s-like dementia syndrome called LATE.
Alzheimer’s disease: definition and diagnostic criteria
Alzheimer’s disease is a progressive dementia with specific Alzheimer neuropathology in the brain. Definite diagnosis requires two types of criteria:
- A clinical picture of progressive dementia consistent with Alzheimer’s, especially memory.
- Confirmation in brain tissue of Alzheimer neuropathology. Strictly, this tissue pathology is “the disease”.
Clinical picture
- Disorientation to place: not knowing exactly where they are, what building, what city.
- Disorientation to time: no longer knowing the day, month, season or year.
- Forgetting daily or recent events, beyond what is common in most people.
- Progressive worsening that disrupts everyday life. This last element is essential for calling it dementia.
Neuropathology
Two abnormal, misfolded protein deposits, each used as a biomarker (Heiko Braak’s work is cited on the slide):
- Biomarker 1, plaques: sticky clumps of beta amyloid, sitting extracellularly between neurons.
- Biomarker 2, tangles: abnormal tau protein, neurofibrillary tangles inside neuronal cell bodies.
Interpretation of these deposits:
- Some plaques and tangles occur in normal healthy ageing brains.
- In Alzheimer’s there are increasingly high levels and an increasingly abnormal distribution for the person’s age. So it is quantity and distribution relative to age, not mere presence, that matters. (Source based on Selkoe, Scientific American; the credit line is cut off on the slide.)
Distribution of plaque pathology, shown on a lateral brain illustration, involves prefrontal cortex, posterior parietal cortex, amygdala, hippocampus, entorhinal cortex and inferior temporal cortex, with the densest stippling over prefrontal, posterior parietal and medial temporal areas. The hippocampus is named after the seahorse it resembles.
Macroscopic and imaging changes, healthy versus Alzheimer’s:
- Whole brain: healthy brains have full plump gyri; the Alzheimer’s brain shows narrowed gyri and widened sulci (cortical atrophy) and is smaller overall.
- Coronal MRI: the hippocampus is visibly smaller in Alzheimer’s and the ventricles are enlarged.
- Overall the figure conveys generalised cortical atrophy plus hippocampal atrophy and ventricular enlargement.
Warning
Transcript flags on the imaging and classification slides: the marker “(1)” on the lower Alzheimer’s MRI is unexplained and has no legend on the slide, and the AT(N) table slide carries no title or source line of its own, simply continuing the classification from the preceding slide.
The AT(N) biomarker classification
Jack et al., 2018. It uses in vivo biomarkers to classify disease status and clinical status. The three markers are:
- A+: amyloid positive scan
- T+: pathologic tau positive scan
- N+: MRI neuropathology (neurodegeneration / neuronal injury) positive
A person is classified by which of A, T and (N) are positive, then cross-classified against cognitive stage (cognitively unimpaired, MCI, dementia):
| Biomarker profile | Cognitively unimpaired | MCI | Dementia |
|---|---|---|---|
| A−T−(N)− | Normal AD biomarkers, cognitively unimpaired | Normal AD biomarkers with MCI | Normal AD biomarkers with dementia |
| A+T−(N)− | Preclinical Alzheimer’s pathologic change | Alzheimer’s pathologic change with MCI | Alzheimer’s pathologic change with dementia |
| A+T+(N)− and A+T+(N)+ | Preclinical Alzheimer’s disease | Alzheimer’s disease with MCI (prodromal AD) | Alzheimer’s disease with dementia |
| A+T−(N)+ | Alzheimer’s and concomitant suspected non-Alzheimer’s pathologic change, cognitively unimpaired | Same, with MCI | Same, with dementia |
| A−T+(N)−, A−T−(N)+ and A−T+(N)+ | Non-Alzheimer’s pathologic change, cognitively unimpaired | Non-Alzheimer’s pathologic change with MCI | Non-Alzheimer’s pathologic change with dementia |
Important
The key reading of the table: amyloid positivity alone is “Alzheimer’s pathologic change”, while amyloid plus tau positivity is “Alzheimer’s disease”. Tau positivity without amyloid is non-Alzheimer’s pathologic change. Cognitive stage is a separate axis, so any profile can occur at any stage.
LATE: a “new” dementia in those over 80
- Many people with dementia fit an Alzheimer’s-type presentation: clear progressive memory loss far beyond that expected for their age.
- Yet some had hippocampal atrophy (“sclerosis”) but not excessive Alzheimer’s pathology, or else far worse symptoms and decline than the observed Alzheimer’s pathology would explain.
- Established in 2019 (Nelson et al.), another protein abnormality is now accepted: an altered “transactive DNA protein” that normally regulates gene expression. This is LATE dementia.
- It does not always come with hippocampal (seahorse) atrophy.
- It may be responsible for half of dementias over age 80, and some cases start earlier. There is no biomarker for it yet.
Resilience, cognitive and brain reserve
Pathology alone does not determine who is demented. Negash et al. (2011): classic pathologies may explain only 25% of dementia; other reasons such as education, social networks, cognitive and physical activities and nutrition may explain resilience or the lack of it.
The two-by-two matrix plots thinking and memory (intact to impaired) against neuropathology / loss of brain function (low to high):
- Healthy: intact thinking, low pathology.
- Resilient: intact thinking despite high pathology.
- Frail thinking: impaired thinking with low pathology.
- Dementias: impaired thinking with high pathology.
Two routes lead into the dementias cell: downward from “resilient” (loss of resilience) and rightward from “frail thinking” (accumulating pathology).
Cognitive reserve and the point of inflection
Stern, 2009, Neuropsychologia 47. Cognitive activity may build cognitive reserve, which may allow individuals with Alzheimer’s pathology to function normally for longer. Plotting memory test score against accumulating plaques and tangles:
- The high-reserve person starts at a higher memory score and stays flat until a marked “point of inflection” well along the pathology axis, after which performance falls steeply.
- The low-reserve person starts lower, stays flat only briefly, then declines more gradually from an earlier point.
- A horizontal threshold marks incident dementia, and both curves eventually converge at high pathology.
So reserve delays the crossing of the dementia threshold rather than preventing the pathology, and decline after the inflection point is faster.
Education as a modifier of pathology
Bennett et al., 2003, Neurology 60, adapted. Decline in thinking plotted against Alzheimer plaque score (0.0 to 3.0) for three education levels:
- High education (22 years) declines least, to about −0.8 at a plaque score of 3.0.
- Average education is intermediate, to about −1.9.
- Low education (15 years) declines most steeply, to about −2.6.
So for the same plaque burden, more years of education is associated with less cognitive decline, and high education also reduces loss of brain tissue in old age. Two caveats from the slide: it may be too late, since we cannot turn back the clock for older people; and early education may not protect against the cognitive impact of tangles, the other Alzheimer cell pathology.
Life-course risk and protective factors
Risk and protective factors act at different points across a life-course timeline from age 0 to 80+, and mid-life and late-life factors carry over and interact with each other.
Risk factors by age
- From age 0: genetic risk factors.
- From about age 10: socioeconomic-status-related factors.
- About age 40 to 60: life habits such as smoking, hypertension and other vascular risk factors, occupational exposure, sensory loss.
- From age 60: life habits such as smoking, vascular risk factors, vascular diseases, depression, head trauma (depression and head trauma are highlighted on the slide).
Protective factors by age
- From about age 10: high education.
- From about age 40: antihypertensive drugs, hearing correction.
- From about age 60: diet of fish and vegetables, low to moderate alcohol, hearing correction, antihypertensive drugs, statins, NSAIDs.
- From about age 60 to 80: rich social network, mental activities, physical activities (highlighted on the slide).
Self-test
- Define dementia as the lecture defines it, and give the three features it always involves.
- Which of dementia’s features does the lecture single out as critical, and why does it matter for distinguishing dementia from other cognitive complaints?
- State the prevalence of Alzheimer’s disease and related dementias at ages under 60, over 65, over 85 and over 90.
- Describe what happened to New Zealand’s population aged 65+ from 1951 to 2051, including when the increase accelerated and why.
- In what three respects do memory changes in ageing differ from memory problems in Alzheimer’s disease?
- Describe the stages of the Alzheimer’s pathological-clinical continuum in order, and how the curve relates to normal ageing.
- List the causes of dementia with their approximate proportions.
- State the two types of criteria required for a definite diagnosis of Alzheimer’s disease, and say which one strictly constitutes “the disease”.
- List the four features of the clinical picture of Alzheimer’s disease, and identify which one is essential for the label “dementia”.
- Distinguish plaques from tangles by protein and by cellular location.
- Since plaques and tangles also occur in healthy ageing brains, what makes them pathological in Alzheimer’s disease?
- Describe the macroscopic and MRI changes seen in an Alzheimer’s brain compared with a healthy brain.
- Explain what A, T and (N) stand for in the AT(N) classification and what the scheme is used for.
- A cognitively unimpaired person has a positive amyloid scan and a negative tau scan. What is their AT(N) label, and how would it change if the tau scan were positive?
- Explain why LATE was proposed as a separate entity, what protein abnormality defines it, and what limits its diagnosis in practice.
- Using the resilience matrix, distinguish a “resilient” person from a person with “frail thinking”, and name the two routes into the dementias cell.
- Predict how a high-reserve and a low-reserve person differ in memory test score as Alzheimer’s pathology accumulates, including what happens after the point of inflection.
- What does the Bennett et al. education graph show for the same plaque burden, and what two caveats does the lecture attach to it?
- List the risk factors acting at each stage of the life-course timeline, from age 0 onwards.
- List the protective factors acting from about age 40 onwards.
- Integrative: a woman in her mid-80s has progressive memory loss and hippocampal atrophy on MRI but only modest amyloid pathology on scan. Drawing on the differential, the AT(N) scheme, LATE and the reserve model, explain the possible accounts of her presentation.
Answers
Reveal answers
- Dementia is not a specific disease but an umbrella term for the symptoms of a group of brain diseases that always impair thought (often memory), always impair everyday activities of daily living, and often involve behavioural and psychological problems.
- Impairment of everyday activities of daily living is flagged as critical. It is the functional consequence, so isolated memory complaints without disrupted daily life do not amount to dementia; the clinical picture slide likewise requires progressive worsening that disrupts everyday life.
- Under 60: 0.01%. Over 65: 10%. Over 85: 25%. Over 90: 34%.
- It rose slowly from about 200 thousand in 1951, then accelerated from around 2011 as the post-war baby boomers reached 65 (around 550 thousand at that point), plateauing near 1,150 to 1,200 thousand by 2041 to 2051. The proportion aged 65+ rose from about 10% to about 25%.
- Magnitude, range and context.
- Preclinical (cognition still near normal and flat), then MCI (the curve separates from the ageing curve), then dementia (steep decline). Normal ageing runs alongside as a gradually declining curve from which the Alzheimer’s curve diverges downwards.
- Alzheimer’s disease about 50%, vascular dementia 15%, Parkinson’s and related dementia 15%, mixed Alzheimer’s plus vascular 10%, other such as alcohol, HIV and CJD 4%, frontotemporal dementia 1%.
- First, a clinical picture of progressive dementia consistent with Alzheimer’s, especially memory. Second, confirmation in brain tissue of Alzheimer neuropathology. Strictly, the tissue neuropathology is the disease.
- Disorientation to place, disorientation to time, forgetting daily or recent events beyond what is common in most people, and progressive worsening that disrupts everyday life. The last is essential for dementia.
- Plaques are sticky clumps of beta amyloid lying extracellularly between neurons. Tangles are abnormal tau protein forming neurofibrillary tangles inside neuronal cell bodies.
- Not their presence but their amount and distribution: in Alzheimer’s there are increasingly high levels and an increasingly abnormal distribution for the person’s age.
- Whole brain: narrowed gyri and widened sulci (cortical atrophy) and a smaller brain overall, versus full plump gyri in health. Coronal MRI: a visibly smaller hippocampus and enlarged ventricles. Together, generalised cortical atrophy plus hippocampal atrophy and ventricular enlargement.
- A is amyloid (positive amyloid scan), T is pathologic tau (positive tau scan), N is MRI neuropathology, that is neurodegeneration or neuronal injury. The scheme uses in vivo biomarkers to classify disease status and clinical status, cross-classified against cognitive stage.
- A+T−(N)−, cognitively unimpaired, which is labelled preclinical Alzheimer’s pathologic change. With a positive tau scan the profile becomes A+T+, labelled preclinical Alzheimer’s disease.
- Because some people over 80 had a clear progressive amnestic dementia with hippocampal atrophy or sclerosis but not excessive Alzheimer’s pathology, or had far worse symptoms and decline than the observed Alzheimer’s pathology explained. It is defined by an altered “transactive DNA protein” that normally regulates gene expression (Nelson et al., 2019). It does not always involve hippocampal atrophy, may account for half of dementias over 80, and there is no biomarker for it yet.
- A resilient person has intact thinking and memory despite high neuropathology; a person with frail thinking has impaired thinking and memory with low neuropathology. The two routes into dementias are downward from resilient (loss of resilience) and rightward from frail thinking (accumulating pathology).
- The high-reserve person starts at a higher memory score and stays flat until a point of inflection well along the pathology axis, then falls steeply. The low-reserve person starts lower, stays flat only briefly and then declines more gradually from an earlier point. Both eventually converge at high pathology, so high reserve delays crossing the incident dementia threshold but decline after the inflection point is faster.
- For the same plaque burden, more education is associated with less decline: 22 years of education declines to about −0.8 at a plaque score of 3.0, average education to about −1.9, and 15 years to about −2.6; high education also reduces loss of brain tissue in old age. Caveats: it may be too late, since the clock cannot be turned back for older people, and early education may not protect against the cognitive impact of tangles.
- From age 0, genetic risk factors. From about age 10, socioeconomic-status-related factors. About age 40 to 60, life habits such as smoking, hypertension and other vascular risk factors, occupational exposure and sensory loss. From age 60, life habits, vascular risk factors, vascular diseases, depression and head trauma.
- From about age 40, antihypertensive drugs and hearing correction. From about age 60, diet of fish and vegetables, low to moderate alcohol, hearing correction, and antihypertensive drugs, statins and NSAIDs. From about age 60 to 80, a rich social network, mental activities and physical activities. (High education acts earlier, from about age 10.)
- Alzheimer’s disease is the single commonest cause at about 50% and fits the progressive amnestic picture, but the mismatch between modest amyloid and marked hippocampal atrophy and symptoms is exactly the pattern that led to LATE being defined, which may account for half of dementias over 80 and has no biomarker yet. On AT(N) she could be A+T−(N)+, labelled Alzheimer’s with concomitant suspected non-Alzheimer’s pathologic change, or A−T−(N)+ if amyloid were read as negative, that is non-Alzheimer’s pathologic change. The reserve model gives a further account: classic pathologies may explain only about 25% of dementia, so low reserve, or loss of resilience in someone previously resilient, could mean modest pathology produces disproportionate impairment. Vascular or mixed disease remains in the differential.