Alzheimers Flashcards
Epidemiology of AD?
Alzheimer’s Disease (AD) predominantly affects the elderly, with age being the primary risk factor, and its prevalence is expected to rise significantly in the coming decades; by 2050, approximately 30% of Europe’s population will be over 60, as projected by the WHO, and a similar trend is observed in the UK, where dementia cases (not limited to AD) are anticipated to increase progressively until 2051.
Prevalence doubles every 5 years after 60 years of age. The mean onset is 80 years of age. Average illness duration is 8 to 10 years. Alzheimer’s Disease is the 5th most common cause of death after IHD, Stroke, COPD and Lower Respiratory Infections
Reversible dementias?
Alzheimer’s Disease (AD) is an irreversible and progressive form of dementia, but before diagnosing it, reversible causes of dementia, which account for 10-15% of cases, must be excluded. Reversible dementia can result from metabolic conditions (e.g., hypothyroidism, drug, or alcohol abuse), depressive pseudodementia (severe depression mimicking dementia with no organic changes, though depression may signal early AD), iatrogenic factors (medication side effects or abuse), and increased intracranial pressure caused by subdural hematomas or brain tumors. These conditions are treatable and must be carefully evaluated to avoid misdiagnosis.
Irreversible dementia?
Once reversible dementias are excluded, attention shifts to irreversible dementias, with Alzheimer’s Disease (AD) being the most common, accounting for 62% of cases. Vascular dementia (VaD), the second most common type, represents 20% of cases and arises from ischemic or hemorrhagic strokes that cause cognitive decline when sufficiently large or numerous, or in critical brain areas. Mixed dementia, a combination of AD and VaD, accounts for 10% of cases and is particularly relevant in elderly populations. Frontotemporal dementia (FTD), a severe genetic condition representing 2% of cases, is the second most common form in individuals under 65 years old and is characterized by diverse molecular and clinical features. Dementia with Lewy bodies, an alpha-synucleinopathy and atypical Parkinsonian disorder, accounts for 4% of cases, while Parkinson’s dementia, developing in late-stage Parkinson’s Disease, represents 2%. Other causes of irreversible dementia comprise the remaining 3%. AD is the leading cause of irreversible dementia across all age groups, with its prevalence increasing significantly with age. In younger individuals, FTD is more common, whereas VaD predominates as the second most frequent type in the elderly.
Genetics of AD?
AD is not classified as a genetic disease, with 95% of cases being sporadic. However, in about 1% of cases, autosomal dominant monogenic mutations are present, including Presenilin 1 (PSEN1), Presenilin 2 (PSEN2), and the Amyloid Precursor Protein (APP). These mutations result in the abnormal metabolism of Amyloid β, a key pathological feature of AD, and typically lead to a worse prognosis due to the likelihood of familial inheritance.
• APP (Amyloid Precursor Protein): A membrane protein cleaved by secretases. Familial APP mutations shift processing toward amyloidogenic pathways, increasing Aβ production.
• Presenilin 1 (PSEN1): A component of secretase involved in APP processing. Mutations favor the production of Aβ1–42, which forms plaques more readily than Aβ1–40.
• Presenilin 2 (PSEN2): Also part of the secretase complex; mutations similarly enhance Aβ1–42 production.
Other genetic factors, such as Apolipoprotein E (APOE), contribute to risk. Homozygosity for the APOE epsilon 4 allele increases the likelihood of developing AD and the severity of the disease. It also heightens the risk of adverse effects during immunotherapy aimed at reducing amyloid deposition. While these mutations and predispositions do not always cause AD, they significantly influence disease progression and treatment response.
Risk factors in AD? What are the concepts of brain reserve and cognitive reserve?
In addition to genetic predispositions, several modifiable risk factors contribute to AD and other neurological conditions, including smoking, obesity, physical inactivity, and stroke, as they all promote neuronal damage. Conditions like hypertension or stroke reduce the amount of healthy neuronal tissue, accelerating the progression of neurodegenerative diseases.
The concepts of brain reserve and cognitive reserve are critical in understanding resilience to AD:
• Brain Reserve: Genetically determined and unchangeable, it includes factors like a large number of synapses and robust dendritic arborization, which can delay the impact of neurodegenerative processes.
• Cognitive Reserve: Developed throughout life via intellectual activities like reading, attending cultural events, and education. It involves dendritic sprouting and synaptic reshaping, allowing individuals to resist clinical manifestations of AD for longer. Cognitive reserve correlates strongly with education, as measured by years of schooling.
The greater the cognitive reserve, the more delayed the onset of AD symptoms, highlighting the protective role of lifelong intellectual engagement.
Pathology of AD?
Alzheimer’s Disease (AD), first described in 1906 by Alois Alzheimer in a 51-year-old woman, is characterized by two key pathological features: extracellular β-amyloid plaque deposition and intraneuronal neurofibrillary tangles formed by hyperphosphorylated tau protein. These changes lead to neuronal damage and death, with cognitive decline beginning when this damage surpasses a critical threshold.
The disease starts with excessive production and misfolding of β-amyloid, which deposits extracellularly due to ineffective clearance. This disrupts synaptic transmission and triggers tau hyperphosphorylation inside neurons, leading to the formation of neurofibrillary tangles and eventual cell death.
The progression of AD begins in the medial temporal lobe, explaining the initial symptom of memory loss. As the amyloid plaques spread to the frontal and parietal lobes, additional cognitive symptoms arise. Tau pathology follows the amyloid deposition but spreads less extensively at early stages. Both amyloid and tau abnormalities must be present to confirm AD.
On a cellular level, normal amyloid aggregates are cleared by macrophages, but misfolded amyloid proteins form oligomers that resist removal, leading to plaque deposition. Hyperphosphorylated tau then disrupts the microtubule structure within neurons, accelerating neuronal loss.
Though similar to systemic amyloidosis, amyloid deposition in AD primarily affects the brain and is often associated with vascular changes, such as cerebral amyloid angiopathy.
Clinical findings in AD?
AD causes a medial temporal lobe dysfunction, so the damage starts in the area in which there is the storage of memory information associated to episodic memory.
As this part of the brain is affected the main manifestation is verbal memory impairment while in the case of a predominantly involved right medial temporal lobe, visual memory impairment is most frequent.
As this clinical signs are not exclusive to AD but also to other diseases which must be kept in mind.
Example of main complaints : losing objects, spatial and time disorientation, repetitive conversations, difficulty recalling names and events.
In some of the earliest phases the individual may notice some subtle changes that the clinical may not using neuropsychological evaluation. This is called subjective memory complaint and is usually in the preclinical phase.
This condition may remain or evolve to mild cognitive impairment where there are clear signs of episodic memory dysfunction but do not affect daily activities.
Daily activities such as going to the bathroom, bathing, eating, dressing, grooming and transferring are taken into consideration.
The passage to dementia is usually preceded or accompanied by involvement of cognitive domains other than episodic memory loss.
What is the mini mental state examination?
To evaluate cognitive function in Alzheimer’s Disease (AD), the Mini Mental State Examination (MMSE) is commonly used. This questionnaire provides a score out of 30, with normal cognitive function scoring 30/30. Patients with AD typically start with scores around 26-27 or 24 and experience rapid decline as the disease progresses.
AD also presents with significant neuropsychiatric symptoms, especially due to damage in specific brain regions. In early stages, involving the frontal lobe, symptoms such as depression and apathy are common. As the disease advances and affects posterior brain regions, patients may experience more severe symptoms, including delusions, hallucinations, and aggressiveness. Additionally, circadian rhythm disruptions—such as early morning awakenings or insomnia—are exaggerated in AD compared to normal aging, further affecting quality of life.
IWG-2 diagnostic criteria?
Most used classification to date. It allows us to associate the biological and clinical data.
- specific clinical phenotype : the presence of an early and significant episodic memory impairment that includes a gradual and progressive change in memory function over 6 month period and objective evidence of a syndrome of the hippocampal type based on impaired performance on specific tests for AD.
- In vivo evidence of AD pathology : decreased amyloid beta together with increased T-Tau or P-Tau in CSF, increased tracer retention on amyloid PET, and AD autosomal domination mutation in PSEN1, PSEN2 or APP.
Pathophysiological markers confirm the presence of AD and include finding CSF amyloid and P-Tau deposition.
Topographical markers include structural MRI and FDG-PET. We an appreciate atrophy of the medial temporal lobe.
Imaging for AD?
FDG-PET : if we compare healthy controls and AD patients we’ll see hypometabolism in the posterior brain. We can also see it in the lateral parietal cortex, hippocampus, posterior cingulate. This combined with episodic memory loss leads to suspicion of AD. This is a topographic markers confirm.
If you inject a radioactive labeled tracer specific for amyloid, AD patients brains light up.
TAU imaging : recent and less common technique. A radioactive labeled tracer is injected and a PET scan identifies the areas of TAU aggregates.
Structural MRI : it shows evident atrophy of the hippocampus. With the loss of the hippocampus there is an increased ventricle size. An important marker in this context is APO-E4, a genetic risk factor, as patients with this allele experience increased early widespread atrophy.
Biomarkers of MCI to AD conversion?
The biomarkers for Alzheimer’s Disease (AD) are also observed in Mild Cognitive Impairment (MCI) and can serve as prognostic factors for progression to AD. Amyloid PET scans show similar amyloid deposition patterns in MCI and AD, and MCI patients with such deposition often progress to AD within 18-24 months. MRI patterns reveal that MCI patients who develop AD show atrophy in specific regions compared to those who remain stable. Similarly, CSF biomarkers—decreased amyloid-beta and increased tau—predict more rapid progression to dementia.
Temporal relationship of markers : amyloid beta decreases in CSF 25 years before symptoms appear, amyloid deposition increases over time, tau pathology stats later correlating with neuronal damage, structural brain changes on MRI occur then finally clinical symptoms become apparent.
The NEJM did a study involving 128 patients (88 with hereditary AD mutation the rest non carriers) confirmed that biomarkers become positive decades before clinical symptoms.
What is EAOD? Early onset AD vs late onset classical AD?
Early Onset AD (EOAD) refers to Alzheimer’s Disease with symptoms appearing before the age of 65, accounting for 5-10% of all AD cases. EOAD included both classical amnestied variants and atypical presentation. While the classic amnestic variant (aEOAD) is common, characterized by diffuse and widespread pathology, many EOAD cases present as atypical phenotypic variants, which are often more focal.
Key differences between EOAD and late-onset AD include:
• Faster and more aggressive progression in EOAD.
• Greater impairment in cognitive functions beyond memory, such as attention, praxis, and visuospatial abilities.
• Increased psychosocial challenges due to the younger age of patients, affecting family and professional life.
These characteristics make EOAD distinct and often more challenging to manage compared to late-onset AD.
Atypical AD?
Atypical AD refers to focal variants of Early Onset Alzheimer’s Disease (EOAD) that affect specific brain regions rather than causing diffuse pathology like the classic amnestic variant. While the underlying biology of amyloid and tau deposition is the same as in classic AD, certain brain networks are more vulnerable, leading to impairments in non-memory cognitive domains. These variants are classified based on the regions involved:
- Posterior Cortical Atrophy —> significant visual spatial deficits.
- Logopenic variant of primary progressive aphasia —> affected the junction of the temporal and parietal lobes. Leads to difficulty retrieving words during speech and inability to repeat long sentences.
- Frontal AD —> affects frontal lobes and main feature is altered attention and executive functions. It’s DDX is with the behavioral variant of FTD. Indistinguishable both by MRI and clinically, lumbar puncture is needed.
Imaging in atypical AD?
The underlying pathology is the one of AD, but these are focal pathologies in which the involvement in the brain is focused on other specific brain regions.
- Posterior cortical atrophy : this is the site of the “where” pathway (dorsal stream), and both the parietal and occipital areas are severely involved. The hippocampus and the medial temporal lobe are relatively spared in these subjects.
- Logopenic variant of Primary Progressive Aphasia : this is aphasia; the damage affects the language dominant hemisphere. The most frequently involved region is the one between the parietal and the temporal lobe, named the “temporoparietal junction.”
- Diffuse/ Classic Amnestic EOAD : widespread atrophy pattern typical of those with aggressive amnestic presentation since the early phases of the disease. In these patients, the hippocampus is involved, and the parietal, frontal and lateral temporal lobes are involved, too.
Posterior cortical atrophy clinical presentation?
PCA is defined as a clinical radiological syndrome. It is most commonly an atypical variant of AD but can be associated to other neurodegenerative conditions as well.
It is characterized by a progressive degeneration in the posterior brain regions that are associated with visual processing and other visuospatial.
As the hippocampus is relatively spared, memory and language are remain intact in the early phases of the disease.
Predominant involvement of either the dorsal or ventral pathway changes the main complaint. The first would be difficulty localizing objects in space, the latter would be visual agnosia.
