Dementia and Alzheimers

Overview of Dementia and Alzheimer’s Disease

• Dementia Definition: gradual onset of a set of symptoms including decline in cognitive ability, judgement, orientation, daily function. Includes loss of intellectual abilities e.g. memory, severe enough to interfere w social or occupational functioning

• Alzheimer’s Disease (AD) Definition: A specific type of dementia, most common cause of dementia in people over the age of $65$ . It is associated with selective damage to brain regions and neural circuits critical for memory and cognition.

Major Types of Dementia

• Vascular Dementia:

  • Cause: Caused by reduced blood flow to the brain due to conditions that damage blood vessels, such as stroke, high blood pressure, and diabetes.

  • Mechanism: Reduced blood flow and oxygen supply lead to brain cell damage and cognitive decline.

  • Characteristics: Difficulties with thinking, planning, and decision-making; potential memory problems; and changes in mood or behavior.

  • Notes: Symptoms vary widely based on the location and severity of brain damage. It can occur alongside Alzheimer’s disease.

• Lewy Body Dementia (LBD):

  • Cause: Accumulation of abnormal protein deposits called Lewy bodies, which are clumps of the protein alpha-synuclein in nerve cells.

  • Characteristics: Decline in thinking ability (attention and planning), movement disorders (similar to Parkinson’s disease), visual hallucinations, sleep disturbances, and fluctuating cognitive function.

• Frontotemporal Dementia (FTD):

  • Cause: Damage to the frontal and temporal lobes of the brain.

  • Age of Onset: Typically affects people between the ages of $45$ and $65$.

  • Characteristics: Behavioral changes, personality shifts, language difficulties, and physical symptoms.

Prevalence and Global Incidence

• UK Statistics (Alzheimer’s Society, 2023):

  • Over $944,000$ people live with dementia in the UK today.

  • Approximately $70,800$ are cases of young-onset dementia (affecting those under age $65$).

• Global Projections for 2050:

  • World Total: Projected to rise to $131.5$ million by 2050 from $46.8$ million in 2015.

  • Americas: $29.9$ million.

  • Africa: $15.8$ million.

  • Europe: $18.6$ million.

  • Asia: $67.2$ million.

Categorization and Diagnosis of Dementia

• Broad Categories:

  • Neurodegenerative: Originally called "irreversible" (e.g., AD, Lewy body, Frontotemporal lobar degeneration, Parkinson disease).

  • Non-neurodegenerative: Potentially "reversible" (e.g., cerebrovascular disease).

  • Note: Elderly patients often present with multiple diseases (comorbidities) accounting for cumulative impairment.

• Evaluation Elements:

  1. Thorough Clinical History.

  2. Neurological Exam: Emphasis on mental status assessment.

  3. Selective Labs: Screen for metabolic/physiologic abnormalities (Basic chemistries, thyroid panel, Vitamin $B_{12}$, Vitamin $D$). Serological studies (antinuclear antibody, HIV-ab, heavy metal screen) for certain patients.

  4. Structural Brain Scan: MRI is preferred over CT (except in specific cases of vascular dementia).

• Barriers to Diagnosis:

  • Misidentifying early symptoms as "normal aging."

  • Maintenance of social skills in early stages.

  • Denial by the patient or family.

  • Social stigma.

  • Lack of definitive screening/diagnostic tests.

Screening Tools and Stages of Progression

• Screening Tests:

  • Clock Drawing Test: Patients are asked to draw a clock face with hour numbers showing a specific time (e.g., $16:40$).

  • Mini-ACE (Mini-Addenbrooke's Cognitive Examination): A short screening test scored out of $30$. A score of $21$ or lower suggests dementia; cut-off scores are generally set at $25$ and $21$.

• Global Deterioration Scale (7 Stages of AD):

  • Stage 1: Cognitively normal; pathological changes starting.

  • Stage 2 (Prodromal): Mild memory loss, indistinguishable from normal forgetfulness.

  • Stage 3 (MCI): Mild Cognitive Impairment. Difficulty finding words or getting lost.

  • Stage 4: Moderate dementia; poor short-term memory; loss of some personal history.

  • Stage 5: Cognition declines; individuals need help with daily life; significant confusion.

  • Stage 6: Severe dementia; requires constant supervision; failure to recognize family; personality changes.

  • Stage 7: Nearing death; motor symptoms, communication loss, incontinence, requires feeding assistance.

Symptom Progression by Stage

• Early Stage: Difficulties with language (PNFA - Progressive Non-Fluent Aphasia) and behavior (BvFTD - Behavioral variant frontotemporal dementia), including apathy and loss of social appropriateness.

• Middle Stage: Changes are obvious to others; inability to perform everyday tasks; increased frustration, anger, and suspicion; creates stress for caregivers.

• Late Stage: Extensive brain damage; physical changes are severe; total dependency for mobility and basic activities; health worsens on multiple fronts.

Molecular Pathophysiology of Alzheimer’s

• Brain Regions Affected: Neocortex, hippocampus, amygdala, and the basal forebrain cholinergic system.

• Amyloid Plaque Formation:

  • Plaques are composed of $40-42$ residue Amyloid-beta ($A\beta$) peptides ($4\,kD$).

  • Derived from Amyloid Precursor Protein (APP), a $110-135\,kDa$ glycoprotein hypothesized to act as a cell surface signaling molecule.

  • APP is cleaved by $\alpha$, $\beta$, and $\gamma$ secretases. $\beta$ and $\gamma$ secretase cleavage generates $A\beta$.

  • $A\beta40$: Soluble form; makes up about $90\%$ of secreted peptides.

  • $A\beta42$ and $A\beta43$: Insoluble forms; highly fibrillogenic and neurotoxic; makes up about $10\%$ of secreted peptides.

  • Aggregation occurs through salt linkages and hydrogen bonds between ionized side chains.

• Presenilins (PS1 and PS2):

  • $43-50\,kD$ proteins with eight transmembrane domains.

  • Mutations in presenilins cause increased production of the neurotoxic $A\beta42$ and $A\beta43$.

• Neurofibrillary Pathology:

  • Affected neurons accumulate tau protein and ubiquitin.

  • Found in cell bodies, dendrites, and dystrophic neurites as neurofibrillary tangles.

• Plasmin:

  • Enzyme involved in degrading amyloid peptides.

  • Hypothesized that lower levels of plasmin in the hippocampus contribute to $A\beta$ accumulation.

Scientific Hypotheses for Alzheimer’s

• Amyloid Cascade Hypothesis:

  • The trigger is the $A\beta$ peptide. Accumulation leads to plaques, triggering inflammatory responses and neuronal death.

  • Sequence: Missense mutations $\rightarrow$ $A\beta42$ production $\rightarrow$ oligomerization/plaques $\rightarrow$ synaptic effects $\rightarrow$ altered ionic homeostasis/oxidative injury $\rightarrow$ kinase alteration/tau tangles $\rightarrow$ widespread cell death.

  • Problems with the theory: Plaque count does not correlate well with cognitive impairment levels; some non-symptomatic individuals have high plaque counts; soluble oligomers may be more responsible for dysfunction than insoluble fibrils.

• Calcium Hypothesis:

  • Dysregulation of intracellular calcium ($Ca^{2+}$) signaling leads to AD lesions.

  • Increased cytosolic calcium triggers the accumulation of $A\beta$, hyperphosphorylation of tau, and neuronal apoptosis.

  • All genes increasing AD susceptibility modulate calcium signaling.

Genetics and Risk Factors

• Early Onset AD: Often familial autosomal dominant disorders caused by mutations in APP, PS1, or PS2.

• Late Onset AD: No specific single mutation is causative, but risk is increased by alleles of apolipoprotein E4 (apoE) and alpha2 macroglobulin.

• Lifestyle Factors: Risk and progression rate can be impacted by regular aerobic exercise, adherence to a Mediterranean-style diet, and social/cognitive stimulation.

Management and Treatment Strategies

• Pharmacologic Treatments (Symptomatic only):

  • Cholinesterase Inhibitors: Donepezil, rivastigmine, galantamine. They prevent acetylcholinesterase from breaking down acetylcholine, increasing its concentration and enhancing communication between nerve cells.

  • NMDA-receptor Antagonist: Memantine.

  • Duration: Medications may improve symptoms for $6$ months to several years but do not alter the overall course of decline.

• Current Research Directions:

  1. Partial inhibition of proteases (secretases) that generate $A\beta$.

  2. Preventing oligomerization or enhancing clearance of $A\beta$.

  3. Anti-inflammatory strategies targeted at the cellular inflammatory response.

  4. Modulating cholesterol homeostasis (cholesterol-lowering drugs are associated with lower incidence).

  5. Chelation of metal ions (zinc and copper) involved in $A\beta$ aggregation.

  6. Stem Cell Therapy: Currently unavailable; complex due to the variety of neuron types needing replacement.

Clinical Realities and Comorbidities

• Diagnosis Communication: Only $45\%$ of people with Alzheimer’s or their caregivers report being told of their diagnosis, compared to over $90\%$ for common cancers.

• Fatality Statistics: $1$ in $3$ seniors dies with some form of dementia.

• Co-existing Medical Conditions:

  • Hospitalization rates are significantly higher for Alzheimer's patients with comorbidities (e.g., Hospital stays per $1,000$ Medicare beneficiaries with Chronic Kidney Disease: $1,042$ with AD vs $592$ without AD).

  • Conditions like Congestive Heart Failure, COPD, and Stroke also show much higher admission rates when AD is present.

• Adverse Health Events:

  • $3$ to $6$ times more likely to develop delirium.

  • $1.6$ to $5$ times more likely to fall.

  • $5$ times more likely to develop new urinary incontinence or pressure sores.

  • $6$ times more likely to develop fecal incontinence.

• Reasons for Hospitalization (Admitting Diagnosis):

  • $26\%$: Syncope, fall, trauma.

  • $17\%$: Ischemic heart disease.

  • $9\%$: Gastrointestinal disease.

  • $6\%$: Pneumonia.

  • $5\%$: Delirium or mental status change.

Prognosis

• Life Expectancy: Average is $4-8$ years after diagnosis for those aged $65+$, though some live up to $20$ years.

• Influencing Factors: Prognosis is worse if diagnosed at an older age. Some research suggests women and those with college-level education may have a longer life expectancy.